Download the PDF

547
Journal of Alzheimer’s Disease 33 (2013) 547–658
DOI 10.3233/JAD-2012-121537
IOS Press
Review
Cognitive Enhancers (Nootropics). Part 2:
Drugs Interacting with Enzymes
Wolfgang Froestl∗ , Andreas Muhs and Andrea Pfeifer
AC Immune SA, EPFL, Lausanne, Switzerland
Accepted 30 August 2012
Abstract. Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease,
schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing,
applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and
psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed
in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To
classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in
particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants,
metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with
amyloid-␤ and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g.,
peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.
Keywords: Alzheimer’s disease, cognitive enhancers, donepezil, enzymes, galantamine, memory, rivastigmine
1. INTRODUCTION
As of August 29, 2012, there are 26,677 entries in
PubMed under the term cognitive enhancers, 26,680
entries under the term nootropic and 242 entries under
the term cognition enhancers. Scifinder lists 5,105
references under the research topic nootropic, 535
references under the term cognitive enhancer, and
9,780 references for cognition enhancers. The Thomson Reuters Pharma database lists 1,106 drugs as
nootropic agents or cognition enhancers and gives zero
results under the term cognitive enhancer. The term
nootropics was coined by the father of piracetam Corneliu Giurgea in 1972/1973 [1, 2], NOOS = mind and
TROPEIN = toward.
∗ Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,
EPFL Quartier de l’innovation building B, CH-1015 Lausanne,
Switzerland. Tel.: +41 21 693 91 21; Fax: +41 21 693 91 20; E-mail:
[email protected].
Nootropics are drugs to treat cognition deficits,
which are most commonly found in patients suffering
from Alzheimer’s disease (AD), schizophrenia, stroke,
attention deficit hyperactivity disorder, or aging. Mark
J. Millan and 24 eminent researchers [3] presented an
excellent overview on cognitive dysfunction in psychiatric disorders in the February 2012 issue of Nature
Reviews Drug Discovery and defined cognition as “a
suite of interrelated conscious (and unconscious) mental activities, including pre-attentional sensory gating,
attention, learning and memory, problem solving, planning, reasoning and judgment, understanding, knowing
and representing, creativity, intuition and insight, spontaneous thought, introspection, as well as mental time
travel, self awareness and meta cognition (thinking and
knowledge about cognition)”.
Since a first review in 1989 on “Families of Cognition Enhancers” by Froestl and Maı̂tre [4], substantial
progress has been made in the understanding of
ISSN 1387-2877/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
548
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
the mechanism(s) of cognitive enhancers. Therefore,
we propose a new classification to assign cognition
enhancing drugs to 19 categories:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Drugs interacting with Receptors (Part 1)
Drugs interacting with Enzymes (Part 2)
Drugs interacting with Cytokines (Part 3)
Drugs interacting with Gene Expression
(Part 3)
Drugs interacting with Heat Shock Proteins
(Part 3)
Drugs interacting with Hormones (Part 3)
Drugs interacting with Ion Channels (nonReceptors) (Part 3)
Drugs interacting with Nerve Growth Factors
(Part 3)
Drugs interacting with Re-uptake Transporters
(Part 3)
Drugs interacting with Transcription Factors
(Part 3)
Antioxidants (Part 3)
Metal Chelators (Part 3)
Natural Products (Part 3)
Nootropics (“Drugs without mechanism”)
(Part 3)
Peptides (Part 3)
Drugs preventing amyloid-␤ aggregation (Part 3)
16.1. Ligands interacting with amyloid-␤
(Part 3)
16.2. Inhibitors of serum amyloid P component
binding (Part 3)
16.3. Vaccines against amyloid-␤ (Part 3)
16.4. Antibodies against amyloid-␤ (Part 3)
Drugs interacting with tau (Part 3)
17.1. Small molecules preventing tau aggregation (Part 3)
17.2. Ligands interacting with tau (Part 3)
17.3. Vaccines against tau (Part 3)
17.4. Antibodies against tau (Part 3)
Stem Cells (Part 3)
Miscellaneous (Part 3)
In Part 1, drugs interacting with receptors were
described [5]. In Part 2, we describe drugs interacting with enzymes and in Part 3, drugs interacting with
targets 3 to 10 and compounds and preparations of
categories 11 to 19.
2. DRUGS INTERACTING WITH ENZYMES
Researchers have been investigating drugs interacting with a wide variety of enzymes in order to
identify valuable cognition enhancers. These enzymes
are:
2.1 Drugs interacting with Acetyl- & Butyrylcholinesterase (AChE & BChE)
2.1.1. Drugs inhibiting AChE and other biological targets
2.1.1.1. Dual AChE inhibitors and
AChE receptor ligands
2.1.1.2. Dual AChE and amyloid-␤
inhibitors
2.1.1.3. Dual AChE inhibitors and
antioxidants
2.1.1.4. Dual AChE and ␤-secretase-1
or ␥-secretase inhibitors
2.1.1.5. Dual AChE inhibitors and calcium channel blockers
2.1.1.6. Dual AChE inhibitors and
cannabinoid receptor antagonists
2.1.1.7. Dual AChE and fatty acid
amide hydrolase inhibitors
2.1.1.8. Dual AChE inhibitors and histamine H3 receptor antagonists
2.1.1.9. Dual AChE and monoamine
oxidase inhibitors
2.1.1.10. Dual AChE inhibitors and
metal chelators
2.1.1.11. Dual AChE inhibitors and Nmethyl-D-aspartic acid receptor channel blockers
2.1.1.12. Dual AChE inhibitors and
platelet activating factor antagonists
2.1.1.13. Dual AChE and serotonin transporter inhibitors
2.1.1.14. Dual AChE and sigma receptor
inhibitors
2.2 Drugs interacting with ␣-Secretase
2.3 Drugs interacting with ␤-Secretase
2.4 Drugs interacting with ␥-Secretase
2.4.1. ␥-Secretase Inhibitors
2.4.2. ␥-Secretase Modulators
2.4.3. Inhibitors of ␥-Secretase Activating
Protein
2.4.4. Notch Pathway Inhibitors
2.5. Drugs interacting with ␤-Hexosaminidase
2.6. Drugs interacting with 11␤-Hydroxysteroid
Dehydrogenase
2.7. Drugs interacting with Calpain
2.8. Drugs interacting with Carbonic Anhydrase
2.9. Drugs interacting with Caspases
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
2.10. Drugs interacting with Catechol-O-methyltransferase
2.11. Drugs interacting with Cathepsin
2.12. Drugs interacting with Cholesterol 24Shydroxylase (CYP46A1)
2.13. Drugs interacting with Cyclooxygenase
2.14. Drugs interacting with D-Amino Acid
Oxidase
2.15. Drugs interacting with Glutaminyl Cyclase
2.16. Drugs interacting with Glyceraldehyde-3Phosphate Dehydrogenase
2.17. Drugs interacting with Glycogen Synthase
Kinase-3␤
2.18. Drugs interacting with Guanylyl Cyclase
2.19. Drugs interacting with Heme Oxygenase
2.20. Drugs interacting with Histone Deacetylase
2.21. Drugs interacting with HMG-CoA Reductase
2.22. Drugs interacting with Insulin-degrading
Enzyme
2.23. Drugs interacting with Kinases ( =GSK-3␤
/
and
=
/ PKC)
2.24. Drugs interacting with Kynurenine MonoOxygenase and Kynurenine Transaminase II
2.25. Drugs interacting with 5-Lipoxygenase
2.26. Drugs interacting with Monoamine Oxidase
2.27. Drugs modulating O-linked N-Acetylglucosaminidase
2.28. Drugs interacting with Peptidyl-prolyl cis-trans
Isomerase D
2.29. Drugs interacting with Phosphodiesterases
2.30. Drugs interacting with Phospholipases A2 and
D2
2.31. Drugs interacting with Plasminogen Activator
Inhibitor
2.32. Drugs interacting with Poly ADP-Ribose Polymerase
2.33. Drugs interacting with Prolyl Endo Peptidase
2.34. Drugs interacting with Prostaglandin D & E
Synthases
2.35. Drugs interacting with Protein Kinase C
2.36. Drugs interacting with Protein Tyrosine Phosphatase
2.37. Drugs interacting with Rac1 GTPase
2.38. Drugs interacting with Ras Farnesyl Transferase
2.39. Drugs interacting with S-Adenosylhomocysteine Hydrolase
2.40. Drugs interacting with Sirtuin
2.41. Drugs interacting with Steroid sulfatase
2.42. Drugs interacting with Transglutaminase
2.43. Drugs interacting with Ubiquitin Carboxylterminal Hydroxylase (Usp14).
549
2.1. Drugs interacting with Acetyl- and
Butyrylcholinesterase
Since the publication of the cholinergic hypothesis of AD by Bartus et al. in 1982 [6], tremendous
efforts have been undertaken to find either selective
acetylcholine receptor agonists (described in Part 1)
or acetylcholinesterase (AChE) inhibitors [7–15]. The
history of the cholinergic hypothesis was traced back
[16]. In retrospect, the latter approach (i.e., AChE
inhibitors) turned out to be more successful than the big
efforts to find selective acetylcholine receptor agonists.
Tacrine
(tetrahydroaminoacridine,
Cognex;
Warner-Lambert, Pfizer) was approved by the Food
and Drug Administration (FDA) in 1993 and was
launched in 1995 for the treatment of AD. It potently
blocks butyrylcholinesterase (BChE) (IC50 = 47 nM)
and AChE (IC50 = 190 nM) [17]. Tacrine has a short
half-life (2–3 hours) and must be administered 4
times a day. The major problem is its severe, though
reversible, hepatotoxicity [17, 18].
Donepezil (Aricept; E2020; co-developed by Eisai
and Pfizer, Fig. 1) was approved by the FDA in November 1996 and was launched in the US in January
1997 for the treatment of mild-to moderate AD. In
October 2006, FDA approval for the treatment of
severe AD was granted. It potently blocked AChE
(IC50 = 23 nM), whereas blockade of BChE was 320
times weaker (IC50 = 7,420 nM) [17]. The Japanese
inventors disclosed values of IC50 = 5.7 nM for AChE
and IC50 = 7,140 nM for BChE (factor 1250) [19].
Donepezil interacts with the active site of AChE and the
peripheral anionic site of the enzyme [20]. Its long terminal disposition half-life of 70 hours supports oncedaily administration [18]. Interestingly, the two enantiomers of donepezil racemize rapidly in vivo [21, 22].
The sales for donepezil reported by Eisai for 2011
totaled USD 1.853 billion (Thomson Reuters Pharma,
update of August 24, 2012).
2,301 publications on donepezil are listed in
PubMed (as of August 29, 2012).
For the synthesis and medicinal chemistry of
donepezil, see [19, 23], for an efficient process for
large-scale synthesis of donepezil [24, 25], and for
molecular modeling of donepezil [26, 27].
Many preclinical and mechanistic reviews have been
published [28–37]. Interestingly, donepezil eliminated
the suppressive effects of amyloid-␤ (A␤)42 on longterm potentiation (LTP) in rat hippocampal slices [38,
39]. Synergistic effects of donepezil and the 5-HT4
receptor agonist RS-67333 on the object recognition were observed in mice [40]. Pharmacokinetic
550
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 1. Launched acetylcholinesterase inhibitors.
considerations for donepezil dosing strategies were
presented [41].
There is extensive literature available on clinical trial
results; see (in chronological order) [42–66]. Broader
considerations of higher doses of donepezil in the
treatment of mild, moderate, and severe AD were communicated recently [67], in particular on the question
of the case of the 23 mg dose [68]. For the effects
of donepezil on levels of cholinesterases in the cerebrospinal fluid (CSF) of AD patients, see [69].
For safety and tolerability of donepezil, see [70–72],
for pharmaco-economics [73–81].
Donepezil significantly improved abilities in daily
lives of young adults with Down syndrome [82] and
in female Down syndrome patients [83], whereas in
children with Down syndrome of age 10–17 years,
donepezil did not show any benefit versus placebo [84].
Donepezil was used for the treatment of patients
with Parkinson’s disease [85–87] and for the treatment
of memory impairment in multiple sclerosis patients
[88].
Many galenical forms have been developed.
Donepezil hydrochloride fine granule formulation was
launched in Japan in September 2001. Donepezil rapid
oral disintegration tablet was launched in Japan in July
2004 and in the US in June 2005. Donepezil oral jelly
formulation was launched in Japan in December 2009.
Donepezil oral sustained release high-dose (23 mg)
tablet formulation was launched in the US in August
2010. The US NDA donepezil once weekly transdermal formulation in collaboration with Teikoku Seiyaku
was submitted in June 2010. A dry syrup formulation
administered by suspending the dry syrup in water
is in pre-registration in Japan. A fast dissolving oral
film strip formulation in collaboration with Applied
Pharma Research and Labtec is in clinical evaluation,
as is donepezil oral rapid disintegration film in collaboration with Kyukyu Pharmaceuticals. Donepezil
transdermal patch with Labtec, donepezil hydrochloride transdermal patch with Nitto Denk and Kowa, and
NAL-8812, a 3-day patch formulation co-developed
with NAL Pharmaceuticals are in preclinical evaluations, as is the Immediate Suspension encapsulation by
ALRISE Biosystems. NAL-8817 is an orally dissolving film formulation of donepezil using the BIO-FX
fast-onset oral cavity drug delivery system technology
in preclinical evaluation (Thomson Reuters Pharma,
update of May 31, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Deuterated donepezil is investigated by the company Deuteria Pharmaceuticals for the potential
treatment of AD (Thomson Reuters Pharma, update
of August 10, 2012).
Donepezil + memantine (ADS-8704, Arimenda;
Adamas Pharmaceuticals), a once-daily fixed dose
combination extended release formulation, is currently
tested in Phase II clinical trials. In May 2012, the FDA
approved Phase III studies in an end-of-Phase II meeting. First clinical results were presented [89] (Thomson
Reuters Pharma, update of July 5, 2012).
Rivastigmine (Exelon, SDZ-ENA-713; SDZ-212713; ENA-713; Novartis, Fig. 1) is a potent BChE
inhibitor (IC50 = 37 nM). It blocks AChE with an
IC50 = 4,150 nM, a factor of 112 times less than BChE
[17]. It forms a carbamoylated complex with the activesite serine inactivating it for about 10 hours producing
a “pseudo-irreversible” inhibition. For an excellent
review on the neurobiology of BChE, see [90, 91].
Rivastigmine was launched for the treatment of mild
to moderate AD in 2000 in the EU and the US and in
2010 in Japan. It was approved for the treatment of
mild to moderately severe dementia associated with
idiopathic Parkinson’s disease. Rivastigmine transdermal patch was launched in the EU in 2007 and in Japan
in 2011 in collaboration with the Japanese licensee Ono
Pharmaceuticals.
Sales for rivastigmine for 2011 were USD 1.067
billion representing a 6% increase on 2010 (Thomson
Reuters Pharma, update of August 24, 2012).
There are currently 1,181 publications on rivastigmine listed in PubMed (as of August 29, 2012).
Several syntheses of rivastigmine were published
[92–96].
Excellent papers on the preclinical characterization
of rivastigmine were communicated [97–102].
Extensive literature exists on the clinical trial
results of rivastigmine in AD (in chronological order)
[103–112]. Rivastigmine at doses of up to 12 mg/day
had useful efficacy in patients with mild-moderate
dementia of the Alzheimer type. Reports from larger
Phase III studies confirmed these findings. The b.i.d.
administration is the more efficacious regimen and had
comparable tolerability to the t.i.d. regimen.
Rivastigmine was evaluated for the treatment of
dementia in Parkinson’s disease [113–120]. Oral
rivastigmine 3–12 mg/day for 24 weeks was significantly more effective than placebo in ameliorating
cognitive and functional decline, including attentional
deficits, in patients with Parkinson’s disease dementia. Rivastigmine was also effective in patients with
dementia with Lewy bodies. Benefits were seen on tests
551
of attention, working memory, and episodic secondary
memory [121]. Rivastigmine was successfully applied
for the treatment of vascular dementia [122–125],
for treatment of hallucinations in Creutzfeldt-Jakob
disease [126], and memory deficits induced by electroconvulsive therapy [127].
For safety and tolerability of rivastigmine, see [50,
74, 128]; for pharmaco-economics [78, 80, 129].
Many reviews exist on results of clinical trials
using the rivastigmine transdermal patch [130–154]
describing enhanced tolerability and significantly less
side effects.
NAL-8822 (NAL Pharmaceuticals) is a one-day
patch formulation of rivastigmine using its Bio-D3
transdermal drug delivery system technology in preclinical evaluation (Thomson Reuters Pharma, update
of May 31, 2012).
Galantamine (Razadyne, Reminyl, Nivalin;
Janssen Pharmaceutica, part of Johnson & Johnson,
Shire and Takeda under license from Sanochemia;
Fig. 1) is an alkaloid extracted from the bulbs of the
Amaryllidaceae family that include daffodils and the
common snowdrop (Galanthea woronowii [155]). It
blocks AChE (E.C. 3.1.1.7) with an IC50 of 800 nM
and BChE (E.C. 3.1.1.8) with an IC50 of 7,320 nM
[17]. Galantamine was launched in 2001 for the
treatment of mild to moderate AD in Europe and the
US and in March 2011 in Japan. In 2005, Johnson
& Johnson launched an extended release capsule
formulation.
The sales of galantamine in 2011 for Johnson &
Johnson were USD 470 million, for Shire USD 40 million, and for Takeda USD 34 million (Thomson Reuters
Pharma, update of August 27, 2012).
There are currently 1,602 publications on galantamine (and galanthamine) listed in PubMed (as of
August 29, 2012).
To a small extent, galantamine is still produced from
snowdrops [156, 157]. However, chemical syntheses
have taken over. A technical process for an efficient
nine-step procedure, which affords (−)-galanthamine
in 12% overall yield, was presented by Sanochemia
[158]. The synthetic schemes from academic laboratories were not scaled up [159–163].
The pharmacological characterization of galantamine was described in depth [164–175]. Galantamine weakly inhibited hERG channels [176].
Interestingly, galantamine not only blocks AChE
and BChE, but also acts as a positive allosteric modulator of nicotinic acetylcholine receptors enhancing
the concentrations of acetylcholine in the brain by a
second mechanism [177–182].
552
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
The pharmacokinetics of galantamine were
reported [183–187].
Many publications described the clinical trial results
of galanthamine in AD (in chronological order)
[188–201 [1]]. Galantamine improved and stabilized
cognitive performance, activities of daily living, and
behavioral symptoms over the course of 6 months,
and its efficacy and tolerability are comparable with
those of other AChE inhibitors (rivastigmine and
donepezil). Galantamine proved to be one of the standard first-line medications for mild-to-moderate AD.
For galantamine in Parkinson’s disease, see [201];
in schizophrenic patients [202]; in vascular dementia
[203].
For safety and tolerability, see [72]; for pharmacoeconomics [78, 80, 204]. The historical development
of galantamine as a clinically used drug was traced
back [205].
Johnson & Johnson developed and launched Razadyne ER (Reminyl XL), an extended release capsule
formulation, in April 2005 in the US. Patients
treated with the extended release formulation had
better overall Alzheimer’s Disease Assessment Scale
(ADAS-cog/11) scores than the placebo group after six
months (Thomson Reuters Pharma, update of March
21, 2012).
NAL-8801 (NAL Pharmaceuticals) is a one day
patch formulation of galantamine using the Bio-D3
transdermal drug delivery system technology in preclinical evaluation (Thomson Reuters Pharma, update
of May 31, 2012).
Memogain (GLN-1062; Galantos Pharma) is a prodrug, the benzoyl ester, of galantamine administered as
an intranasal formulation. Memogain has a more than
15 times higher bioavailability in the brain than the
same dose of galantamine. It is cleaved enzymatically
to galantamine [206]. It is in Phase I since November
2011 (Thomson Reuters Pharma, update of December
28, 2011).
Huperzine A (Cerebra; Shanghai Institute of Materia Medica; Fig. 1) is a natural Lycopodium alkaloid
found in extracts from Huperzia serrate [207]. It was
launched in China for the treatment of AD in 1995. The
drug is administered in low oral doses of 0.1 mg four
times a day. Huperzine A blocked AChE with an IC50
of 82 nM and BChE with an IC50 of 74.43 ␮M [208,
209]. (−)-Huperzine A is 35-fold more potent that (+)Huperzine A (Ki = 6.2 nM and 210 nM, respectively
[210]), corroborating earlier Ki values of 8 nM and
300 nM [211]. Molecular modeling studies revealed
that huperzine A binds to the bottom of the binding
cavity of AChE with its ammonium group interacting
with Trp-84, Phe-330, Glu-199, and Asp-72 (catalytic
site) and to the opening of the gorge with its ammonium group interacting with Trp-279 (peripheral site)
[212]. Tyr-337 is essential for inhibition of recombinant human AChE by huperzine A [213]. The X-ray
structures of Torpedo californica AChE complexed
with (+)-huperzine A and (−)-huperzine B was presented [214].
Currently huperzine A is produced in large scale
from natural sources, in particular from Phlegmariurus squarrosus, a member of the Huperziaceae [215],
although several chemical synthesis schemes were
worked out [208, 216–222]. A large-scale synthetic
route resulted from a joint venture by process chemists
of Shasun Pharma (UK and India), Rhodia Pharma
(USA), and Debiopharm (Switzerland) [223].
There are currently 358 publications on huperzine
A listed in PubMed (as of August 29, 2012).
Excellent reviews on the pharmacology of
huperzine A have been published (in chronological
order) [224–230]. In particular, the neuroprotective effects of huperzine A have been investigated
in great detail, e.g., protective effects against A␤associated neurotoxicity [231–235]. Huperzine A dose
dependently increased secretory amyloid-␤ protein
precursor (A␤PP) release suggesting a modulatory
effect of huperzine A on ␣-secretase activity [236,
237]. These findings were confirmed independently
[238, 239]. This mechanism seems to play via
Wnt/␤-catenin signaling. Chronic administration of
huperzine A to double transgenic mice led to an
increase in ADAM10 and a decrease in ␤-secretase-1
and A␤PP695 protein levels [240]. Recently huperzine
A was also evaluated in triple transgenic mice confirming the improvement of cognitive performance
and the non-amyloid pathway activation [241].
Reviews on results of clinical trials of huperzine A
were published [242–244]. A Phase II clinical study
in 210 AD patients treated with either placebo, 200 ␮g
bid, or 400 ␮g bid of huperzine A (70 patients per arm)
showed no effect in the 200 ␮g group, but huperzine
A 400 ␮g bid showed a 2.27 point improvement in
ADAS-cog at 11 weeks versus a 0.29 decline in the
placebo group (p = 0.001) [245] (Thomson Reuters
Pharma, update of February 20, 2012).
The company Xel Pharmaceuticals (Draper, Utah) is
developing the once-weekly sustained release transdermal patch formulation XEL-001HP. This formulation
is currently tested in a Phase I clinical trial in
China since September 2008. Xel Pharmaceuticals
is also investigating the sustained release topical gel
formulation XEL-001HG in preclinical evaluation
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
(both Thomson Reuters Pharma, update of March 14,
2012).
Novartis chemists synthesized novel analogues of
huperzine A. The program was terminated [246].
WIN-026 (INM-176, KR-WAP-026; WhanIn under
license from Scigenic & Scigen Harvest) is an AChE
inhibitor with antioxidant and anti-A␤ properties containing a 95% extract of Angelica gigas Nakai in the
pre-registration phase [247]. In June 2008, a Phase
III clinical trial for the treatment of AD was initiated, which was completed by May 2011. The results
were submitted to the Korean FDA. Launch is expected
for the second half of 2012. The memory ameliorating effects of INM-176 in mice were described [248]
(Thomson Reuters Pharma, update of May 30, 2012).
Posiphen (the (+)-enantiomer of phenserine, QR
Pharma under license from TorreyPines Therapeutics,
Fig. 2) is in Phase II clinical trials for the oral treatment of AD since June 2009. It was effective to lower
A␤ levels in cell cultures and in mice [249]. Interestingly, posiphen also blocked the expression of brain
␣-synuclein [250, 251]. Posiphen is a candidate drug to
lower CSF A␤PP, A␤ peptide, and tau levels in humans
[252] (Thomson Reuters Pharma, update of July 25,
2012).
Shen Er Yang (Changchun Huayang High
Technology Co Ltd., Shanghai, Fig. 2) is a
tablet formulation of 1,2,3,4,5,6,7,8-octohydro9-phenylacetamidoacridine, a dual cholinesterase
inhibitor in Phase II clinical trials since March 2011
(Thomson Reuters Pharma, update of April 18, 2012).
Methanesulfonyl fluoride (SeneXta under license
from the University of Texas at El Paso, Fig. 2) is an
AChE inhibitor in Phase I clinical trials for AD and
post-stroke cognitive impairment. A Phase II clinical
trial for AD was planned for 2011. For the inhibition
of BChE by methanesulfonyl fluoride, see [253]; for
the inhibition of AChE [254]. Learning and memory
enhancing effects were described [255–258]. A report
on a double-blind, placebo-controlled study of safety
and efficacy in 5 men and 10 women (60–82 years) with
Mini-Mental State Examination (MMSE) scores of
9–24, who had senile dementia of the Alzheimer type,
was published. Methanesulfonyl fluoride improved
cognitive performance as measured by the MMSE,
ADAS-cog, Global Deterioration Scale, and the Clinical Interview Based Impression of Change [259]
(Thomson Reuters Pharma, update of June 28, 2012).
There are currently many cholinesterase inhibitors
in preclinical evaluation (in alphabetical order):
Bisnorcymserine (QR Pharma, under license from
TorreyPines Therapeutics; Fig. 2) is a dual BChE and
553
A␤PP inhibitor. An IND was cleared by the FDA in
December 2010. The inhibition of serum BChE by
bisnorcymserine was reported [260]. For the crystal
structure of the complex, see [261] (Thomson Reuters
Pharma, update of July 25, 2012).
Bis-(7)-tacrine (Mayo Foundation; Fig. 2) was
one of the first homodimers reported in the literature with increased potency as AChE inhibitor
(IC50 = 0.4 nM with significantly less affinity to BChE
(IC50 = 390 nM, selectivity for AChE is a factor of 980)
[262]. For a more detailed description of bis(7)-tacrine,
see section 2.1.1.5. Dual AChE inhibitors and calcium
channel blockers.
FS-0311 (Shanghai Institute for Materia Medica;
Fig. 2) is a bis-huperzine B derivative with similar
potency for the inhibition of AChE as donepezil but
higher potency than huperzines A and B. It antagonized cognitive deficits induced by scopolamine or by
transient brain ischemia [263].
Huprines (tacrine-huperzine A hybrids, Fig. 2)
were presented by scientists of the University of
Autonoma de Barcelona [264–269] and independently
from the University of Hong Kong [270]. French scientists also significantly contributed to novel huprine
derivatives [271–273].
The best characterized huprines are huprine-X
(3-chloro-9-ethyl), huprine-Y (3-chloro-9-methyl,
see Fig. 2), and huprine-Z (3-fluoro-9-methyl). They
are very potent AChE inhibitors with Ki values of
0.026 nM for huprine-X and 0.033 nM for huprine
Y versus 31 nM for tacrine, 1.1 nM for donepezil,
and 4.6 nM for huperzine A [267]. Other scientists
measured IC50 values of 0.78 nM for (±)-huprineY and 4.58 nM for (±)-huprine-Z in human AChE
preparations [274]. (±)-Huprine-X is an agonist at
M1 muscarinic acetylcholine receptors (Ki = 338 nM)
and at M2 mAChRs (Ki = 4.66 ␮M) [275]. The binding of huprine-X to Torpedo californica AChE was
resolved in an X-ray structure at 2.1 Å resolution
[276]. Huprine-X facilitated learning and memory in
the Morris water maze [277]. Chronic treatment of
Tg2576 (A␤PPswe ) mice and of 3xTgAD mice with
0.12 ␮mol/kg huprine-X i.p. for 21 days caused a significant reduction of insoluble A␤40 by 40% (p < 0.05)
in the hippocampus of 3xTgAD mice while showing
no effect in A␤PPswe mice [278]. Additional data on
huprine X in triple transgenic mice were disclosed
recently [241].
Another way to create huperzine A-tacrine hybrids
is to link the primary amino group of huperzine A to the
primary amino group of tacrine with methylene groups
[279]. The best compounds showed Ki values against
554
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 2. Acetylcholinesterase inhibitors in development or in preclinical evaluation.
human AChE of 6.4 nM versus 0.026 for huprine-X.
A group of Spanish and Italian scientists described
huprine-tacrine heterodimers [280, 281].
Dimerization of an inactive fragment of huperzine
A led to bis-(12)-hupyridone (Hong Kong University, Fig. 3) displaying an IC50 = 52 nM versus 115 nM
for huperzine A [282]. The tether length of 12-13
methylene groups is consistent with simultaneous
binding to both the catalytic and the peripheral site
of AChE (see Fig. 5). Bis-(12)-hupyridone may also
act via ␣7 nicotinic acetylcholine receptors [283].
NP-0336 (Noscira) is a BChE inhibitor in preclinical
evaluation (Thomson Reuters Pharma, update of July
19, 2011). The structure was not communicated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
555
Fig. 3. Acetylcholinesterase inhibitors in preclinical evaluation II.
Fig. 4. Dual acetylcholinesterase and muscarinic M2 ACh receptor blocker.
SPH-1285 (Sanochemia Pharmazeutika, formerly
Waldheim Pharmazeutika; Fig. 3 shows SPH-1286)
is a neuroprotective derivative of galantamine for the
potential treatment of glaucoma (Thomson Reuters
Pharma, update of January 3, 2012).
The most potent AChE inhibitor is the molecule
syn-1 (Fig. 3) with Kd of 77 fM synthesized at the
Scripps Research Institute linking a tacrine part via
click chemistry to a phenanthridium unit. The tacrine
part is binding to the catalytic site (see Fig. 5), the
556
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 5. Indole-tacrine heterodimers binding simultaneously to the
catalytic and the peripheral anionic site of acetylcholinesterase
[381]. With permission from ACS Publications.
phenanthridium piece is located at the peripheral site
(see Fig. 5) [284].
Many new scaffolds for AChE inhibitors were
discovered recently, such as benzoxazolinones [285],
indolizinoquinoline [286], isoindoline-1,3-diones
[287], pyrrolo isoxazol benzoic acid derivatives [288],
pyrrolo thiazoles [289], quinazolines [290], and
quinoline derivatives [291] acting as AChE inhibitors.
Also tacrin-ferulic acid-nitric oxide (NO) donor
trihybrides were presented [292].
Excellent reviews describe quantitative structure
activity relationships (QSAR) [293, 294], virtual
screening techniques [295], and the use of support vector machines for a classification of AChE inhibitors
[296]. High throughput screening and molecular
modeling for novel AChE inhibitors was discussed
[297].
The development of many AChE inhibitors was
terminated (in alphabetical order) of amiridin (ipidacrine hydrochloride; Nikken Chemicals [298–300]),
AP-2238 (University of Bologna [301–303]), BZYX
(Zhejiang University), CI-1002 (Parke-Davis, now
Pfizer), CHF-2822 and CHF-2957 (Chiesi), EN-101
(an orally active 20-base antisense oligonucleotide
directed against an AChE sequence; Amarin under
license from Yissum [304]), eptastigmine (MF-201;
Mediolanum [305–309], ER-127528 (Eisai), F-3796
(Pierre Fabre), FR-152558 (Fujisawa), galantamine
liposomal (Sanochemia), ganstigmine (CHF-2819;
Chiesi [310–315], Hoe-065 (Hoechst, now sanofi
[316–318], HP-290 (Hoechst, now sanofi), icopezil
(CP-118954; Pfizer [319]), JES-9501 (dehydroevodiamine hydrochloride, DHED; Jeil Pharmaceuticals
in collaboration with Seoul Univ.), LB-1003 (Lifelike
Biomatic), metrifonate (BAY-a-9826, ProMen; Bayer
[320–324]; MF-268 and MF-8615 (Mediolanum),
MHP-133 (Medical College of Georgia), mimopezil
(DEBIO-9902, ZT-1; Debiopharm under license from
the Shanghai Institute of Materia Medica; a once–daily
prodrug, a Schiff base of huperzine A with 2-hydroxy3-methoxy-5-chloro-benzaldehyde [319], NP-7557
(Nastech [325]), NXX-066 (Astra), P26 (Phytopharm), P-10358, P-11012, P-11149, and P-11467
(Hoechst Marion Roussel, now sanofi), phenserine
and (-)-phenserine (Axonyx under license from NIH,
Daewoong Pharmaceuticals [326–329], of controlled
release and transdermal formulations of physostigmine (Forest Laboratories, Lohmann Therapie Systeme [330–332], protexia (PEG-rBChE; PEGylated
recombinant human butyryl-cholinesterase; PharmAthene under license from Nexia Biotechnologies; a
protein produced in the milk of goats in a pegylated
formulation; the development as post-exposure therapy
for chemical nerve agent, currently in Phase I trials, is
ongoing [333, 334]), Ro-46-5934 (Roche; a dual AChE
inhibitor and M2 muscarinic acetylcholine receptor
antagonist), RS-1439 (Sankyo; a dual AChE and serotonin re-uptake inhibitor), S-9977 (Servier; a dual
AChE and serotonin re-uptake inhibitor), SDZ-ENX792 (Sandoz, now Novartis), SM-10888 (Sumitomo
[335–337]), SPH-1359 (Sanochemia), stacofylline
(S-9977; Servier [338–341]), suronacrine (HP-128;
Hoechst, now sanofi [342, 343]), T-82 (SS Pharmaceutical, a subsidiary of Boehringer Ingelheim and Arena
[344, 345]), tolserine (Axonyx under license from
NIH [346–349], UCB-11056 (UCB), velnacrine (HP029; Hoechst, now sanofi [350, 351]), of zanapezil
(TAK-147; Takeda [352, 353] and of zifrosilone
(MDL-73745, Hoechst Marion Roussel, now sanofi
[354–356]).
2.1.1. Drugs inhibiting AChE and other
biological targets
Tremendous efforts have been undertaken to combine AChE inhibition and interaction with multiple
targets thought to be responsible for AD pathogenesis
to create “multi-target-directed ligands” [357–370].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
2.1.1.1. Dual AChE inhibitors and AChE receptor
ligands. Caproctamine (University of Bologna;
Fig. 4) is a potent AChE inhibitor (Ki = 104 nM) and
a competitive M2 muscarinic acetylcholine receptor
antagonist (Kb = 410 nM) [371].
MHP-133 (Medical College of Georgia; Fig. 4) is an
AChE inhibitor interacting with M1 muscarinic acetylcholine, 5-HT4 and I2 imidazoline receptors [372,
373].
Ro-46-5934 (Hoffmann-La Roche, Fig. 4) is a dual
AChE inhibitor and M2 AChR antagonist for the
potential treatment of AD. The development was discontinued [374].
An attempt to combine tacrine and xanomeline led
to hybride compounds displaying potent acetyl and
BChE inhibition (pIC50 ’s of 8.2 and selectivity ratio
of 1.0). The hybrids did not bind as agonists to the
orthosteric muscarinic acetylcholine M1 receptor but
as antagonists to an allosteric site of the M1 AChR
thereby reducing the amount of acetylcholine [375].
2.1.1.2. Dual AChE and amyloid-β inhibitors. AChE
colocalizes with A␤ peptide deposits in the brains
of AD patients and promoted A␤ fibrillogenesis by
forming stable AChE-A␤ complexes. AChE bound
through its peripheral site to the A␤ nonamyloidogenic
form and acted as a pathological chaperone inducing
a conformational transition to the amyloidogenic form
[376–380].
One approach is to design ligands binding to both
the catalytic as well as to the peripheral anionic site of
AChE inhibitors (Fig. 5) [381].
After first attempts [301, 302, 371, 382–384] an
important breakthrough was achieved with NP-61.
NP-61 (NP-0361; Noscira, previously Neuropharma) is a once-daily dual binding site AChE and
A␤ secretion inhibitor currently in Phase I clinical
trials for the treatment of AD. The structure was
not disclosed, but is probably a combination of
6-chloro-tacrine (binding to the catalytic binding site)
linked via a methylene bridge from the primary amine
to the amide nitrogen of indole propionamide binding
at the peripheral binding site [381]. Key biological
data on NP-61 were published: inhibition of AChE:
IC50 = 20 pM, inhibition of BChE: IC50 = 2.9 nM,
inhibition of A␤40 aggregation with human AChE in
the thioflavin T test: IC50 = 2 ␮M, inhibition of A␤40
aggregation without AChE in the thioflavin T test:
49% at 100 ␮M [385, 386]. NP-61 was able to reverse
cognitive impairment tested in the Morris water maze
and to reduce plaque load in cortex and hippocampus
of 6 month-old human A␤PP (Swedish mutation)
557
transgenic mice treated once daily by oral gavage
for three months (the doses were not communicated)
(Thomson Reuters Pharma, update of May 10, 2012).
IDN-5706, a hyperforin derivative, decreased the
content of AChE associated with different types of A␤
plaques in 7-month-old double A␤PPSWE /PS1 transgenic mice after treatment with IDN 5706 for 10 weeks
[387]. See also Part 3, Chapter 13. Natural Products.
IQM-622 (Neuroscience Group and CSIC, Madrid;
Fig. 6) significantly decreased the brain A␤ deposits
after treatment of A␤PP/PS1 mice for four weeks. It
promoted the degradation of intracellular A␤ in astrocytes and protected against A␤ toxicity in cultured
astrocytes and neurons (chemistry: [388]; biology:
[389]).
This is an area of research with numerous novel
contributions presenting new piperidinium-type compounds [390], new piperidine derivatives [391],
donepezil-type inhibitors [392], novel pyrano[3,2c]quinoline-6-chlorotacrine hybrids [393], pyridinylidene hydrazones [394], novel bis(7)-tacrine derivatives
[395], hybrid compounds combining donepezil and
AP2238 [303], heterodimers of enantiopure huprine
X or Y and donepezil-type derivatives [396],
2,4-disubstituted pyrimidine derivatives [397, 398],
novel triazole-containing berberine derivatives [399],
huprine-tacrine heterodimers [400, 401], isaindigotone derivatives [402], and oxoisoaporphine-based
inhibitors [403]. Berberine derivatives act as multifunctional agents of antioxidant, inhibitors of AChE,
BChE, and A␤ aggregation [404].
Bisnorcymserine (QR Pharma, under license from
TorreyPines Therapeutics; see Fig. 2) is a dual BChE
and A␤PP inhibitor.
2.1.1.3. Dual AChE inhibitors and antioxidants.
Lipocrine (University of Bologna; Fig. 6) is a combination of 6-chlorotacrine with ␣-lipoic acid [405].
It has been shown that ␣-lipoic acid is an universal
antioxidant [406–408], which protected rat cortical
neurons against cell death induced by A␤. Lipocrine
inhibited AChE with an IC50 of 0.25 nM and BChE
with 10.8 nM within 1 minute. It inhibited the aggregation of A␤ with an IC50 of 45 ␮M and showed
significant antioxidant activity against formation of
reactive oxygen species in SH-SY5Y cells after treatment with tert.-butyl hydroperoxide at 5 ␮M (p < 0.01),
10 ␮M (p < 0.001), and 50 ␮M (p < 0.001) [409].
Memoquin (University of Bologna; Fig. 6) is a
combination of the polyamine amide caproctamine
[371] showing AChE and M2 muscarinic ACh receptor blocking properties with a 1,4-benzoquinone
558
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 6. Dual acetylcholinesterase inhibitors with amyloid-␤ inhibitor, antioxidant, BACE-1 inhibitor, and calcium channel blocker activities.
functionality derived from coenzyme Q or idebenone
as a radical scavenger [366, 410, 411]. It inhibited
AChE with an IC50 of 1.55 nM, human AChE-induced
aggregation of A␤40 with an IC50 of 28.3 ␮M and
A␤42 self-aggregation with an IC50 of 5.93 ␮M.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is the
enzyme responsible for the regeneration and maintenance of the CoQ-reduced state. Memoquin is a good
substrate for NQO1 with a Km of 12.7 ␮M. In addition,
memoquin also effectively blocked ␤-secretase-1 with
an IC50 of 108 nM. The compound reduced the number of A␤ plaques in transgenic AD11 mice after oral
administration and rescued behavioral deficits in an
object recognition test in transgenic AD11 mice [412].
Introduction of methyl groups in the ␣-position of
the terminal benzylamine moieties (Fig. 6; Memoquin,
R = Me, both in (R)-configuration) led to an improved
derivative (inhibition of AChE with IC50 of 0.5 nM;
inhibition of human AChE-induced aggregation of
A␤40 with IC50 of 9.34 ␮M [413, 414].
Combination of the 2,5-diamino-benzoquinone
scaffold with curcumin derived substituents is another
way to multitarget-directed ligands [415].
Dual-acting drugs with extremely potent AChE
inhibiting activity and antioxidant properties were presented [416]. Hybrides between 6,8-dichlorotacrine
and melatonin showed an IC50 of 8 pM against
human AChE and potent peroxyl radical absorbance
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
capacities of 2.5-fold the value of Trolox in the oxygen
radical absorbance capacity assay using fluorescein
(ORAC-FL). Full experimental details were provided [417]. N-acylamino-phenothiazines are selective
BChE inhibitors and protected neurons against exogenous and mitochondrial free radicals [418, 419]. A
combination of tacrine and ferulic acid was described
[420] as were novel piperazine derivatives [421].
Berberine derivatives act as multi-functional agents of
antioxidant, inhibitors of AChE, BChE, and A␤ aggregation [422].
2.1.1.4. Dual AChE and β-secretase-1 or γ-secretase
inhibitors. Memoquin (University of Bologna, Fig. 6)
is a potent inhibitor of AChE with an IC50 of 1.55 nM
and of ␤-secretase-1 with an IC50 of 108 nM (see previous section 2.1.1.3.).
Coumarin derivatives are also dual human AChE
and ␤-secretase-1 inhibitors [423]. Inhibitions of
AChE with IC50 of 180 nM and of ␤-secretase-1 with
IC50 of 150 nM were measured.
Researchers from the Shanghai Institute of Materia Medica presented a dual inhibitor of AChE:
IC50 = 1.83 ␮M and of ␤-secretase-1: IC50 = 0.567 ␮M
[424].
A tacrine-chromene derivative with cholinergic,
antioxidant, A␤ reducing, and BACE1 inhibiting
properties showed the following values: AChE:
IC50 = 75 nM, BChE: IC50 = 1 nM, ␤-secretase-1:
IC50 = 2.8 ␮M [425]. Quinoxaline-based hybrid compounds with AChE, histamine H3 receptor, and
␤-secretase-1 inhibitory activities were described
[426].
Galantamine-based hybrid molecules with AChE,
BChE, and ␥-secretase inhibiting activities have been
presented recently [427].
2.1.1.5. Dual AChE inhibitors and calcium channel blockers. Bis(7)-tacrine (Mayo Foundation, see
Fig. 2), first synthesized in 1996 [262], is a very
potent AChE inhibitor (IC50 = 0.4 nM) with significantly less affinity to BChE (IC50 = 390 nM, selectivity
for AChE by a factor of 980). Bis(7)-tacrine was
extensively characterized. It reversed AF64A-induced
deficits in navigational memory in rats [428]. It protected against ischemic injury in primary cultured
mouse astrocytes [429]. It reduced hydrogen peroxideinduced injury in rat pheochromocytoma cells [430]. It
showed inhibitory action on N-methyl-D-aspartic acid
(NMDA) receptors with an IC50 of 0.763 ␮M [431].
Bis(7)-tacrine significantly reduced the augmentation
of (L-type) high-voltage activated inward calcium
559
currents induced by A␤ [432]. For an excellent review,
see [433].
ITH-4012 (TK-19; CSIC Madrid; Fig. 6) is an
AChE inhibitor with an IC50 of 0.8 ␮M [434]. It caused
an elevation of the cytosolic concentration of Ca2+
in fura 2-loaded bovine chromaffine cells from concentrations of 10 to 250 nM, which was related to the
induction of protein synthesis relevant for cell survival.
This cytoprotective action of ITH-4012 was reversed
by the protein synthesis inhibitor cycloheximide.
ITH-12118 (CSIC Madrid; Fig. 6), a tacripyrine,
combines tacrine and a L-type voltage-dependent calcium channel blocker of the nimodipine type. The
synthetic work was described in [435, 436] and the
extensive biological characterization in [437] showing that ITH12118 could be a paradigmatic multitarget
compound having selective brain effects with smaller
peripheral side effects. Additional chemical and pharmacological studies were published [438].
The development of NP-34 (or NP-04634; Noscira,
formerly Neuropharma), a natural product derived
from the marine sponge Aplysina cavericola with calcium channel blocking and AChE inhibiting properties
was terminated [439].
2.1.1.6. Dual AChE inhibitors and cannabinoid receptor antagonists. CB1 receptor antagonists increased
ACh release in certain brain areas including cortical regions and the hippocampus [440]. The CB1
antagonist scaffolds of diaryl-pyrazolines and diarylimidazoles [441, 442] were combined with tacrine.
Compound 20 (Solvay, now Abbott, Fig. 7) displayed
an IC50 of 316 nM for acetylcholinesterase and a Ki
of 48 nM for CB1 receptors. The Ki for CB2 receptors
was >1 ␮M [443].
2.1.1.7. Dual AChE & fatty acid amide hydrolase inhibitors. In regions of A␤-enriched neuritic
plaques an increased activity of the enzyme fatty
acid amide hydrolase (FAAH) was selectively demonstrated [444]. Inhibitors of FAAH may regulate
endocannabinoid signaling and may counteract neuroinflammation. First dual cholinesterase and FAAH
inhibitors were synthesized at the University of
Bologna [445]. One carbamate derivative (shown in
Fig. 7) displayed IC50 ’s of 50 nM for FAAH, 74.9 nM
for human AChE, and 1.57 nM for human BChE.
MIQ-001 (Meta-IQ Aps) is a fatty acid metabolism
inhibitor for the potential treatment of AD. A Phase
I healthy volunteer study was performed with doses
from 6 to 100 mg/day starting in February 2010. No
side-effects were observed. Meta-IQ generated excel-
560
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 7. Dual acetylcholinesterase & fatty acid amide hydrolase inhibitor, dual acetylcholinesterase inhibitor & cannabinoid, and histamine H3
receptor antagonists.
lent preclinical data showing efficacy in restoration of
short and long term memory in an AD mouse model
(Thomson Reuters Pharma, update of June 25, 2012).
The structure was not communicated.
The development of AMR-109 (Amarin Corp.,
ultra-pure eicosapentanoic acid), a modulator of
omega-3 fatty acids, was terminated. For the neuroprotective effects of eicosapentenoic acid against
A␤ induced impairment of LTP and memory, see
[446–448]. For a review on polyunsaturated farry acids
as cognitive enhancers see [449].
2.1.1.8. Dual AChE inhibitors and histamine H3 receptor antagonists. FUB833 (Freie University of Berlin;
Fig. 7) is a potent AChE inhibitor (IC50 = 2.6 nM),
BChE inhibitor (IC50 = 8.8 nM), hH3 receptor antagonist (Ki = 0.33 nM) inhibiting also histamine Nmethyltransferase (HMT with IC50 = 48 nM) [450].
University of Parma medicinal chemists described
potent dual non imidazole histamine H3 receptor antagonists and AChE inhibitors [451]. Quinoxaline-based
hybrid compounds with AChE, histamine H3 receptor,
and ␤-secretase-1 inhibitory activities were described
[452].
2.1.1.9. Dual AChE and monoamine oxidase
inhibitors. Increased monoamine oxidase (MAO) B
activity was found in AD brains [453]. A combination
of AChE and of MAO B inhibitors in one molecule
was attempted already in 1996 [454, 455]. The
breakthrough was achieved with Ladostigil.
Ladostigil (TV-3326; Avraham Pharmaceuticals
under license from Yissum Research Development,
a wholly owned company of the Hebrew University
of Jerusalem; Fig. 8) combines the carbamate moiety
of the BChE inhibitor rivastigmine with the propargylamine pharmacophore of the MAO-B inhibitors
selegiline and rasagiline. Ladostigil is more potent
against BChE (IC50 = 1.7 ␮M) than against AChE
(IC50 = 51 ␮M). It is a central nervous system (CNS)selective inhibitor of MAO-A and MAO-B with
little inhibition of liver and small intestine MAO.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
561
Fig. 8. Dual acetylcholinesterase and monoamine oxidase inhibitor or metal chelator properties.
Propargylamines are irreversible inhibitors of MAO,
therefore the long-term daily administration results in
a cumulative effect. 50 ␮mol/kg given daily for 7 and
14 days inhibited both MAO-A and MAO-B by >60%.
80% inhibition of the brain enzymes was achieved with
a dose of 75 ␮mol/kg given once daily for 2 weeks
[456]. Ladostigil was extensively characterized [357,
457–472].
Ladostigil is currently in Phase IIb clinical trials
in 190 patients in Europe since December 2010 for
the oral treatment of AD. In February 2012 a Phase
II trial was initiated in Israel and Europe in patients
suffering from mild cognitive impairment (Thomson Reuters Pharma, update of May 18, 2012). See
also section 2.26. Drugs interacting with Monoamine
Oxidase.
Spanish medicinal chemists described potent dual
cholinesterase and MAO inhibitors [473–475].
2.1.1.10. Dual AChE inhibitors and metal chelators.
HLA20A (Technion Haifa; Fig. 8) is a combination
of an 8-hydroxy-quinoline metal chelator, which was
carbamoylated at the 8-hydroxy function to interact
with AChE as does rivastigmine [476, 477]. Inhibition
of AChE was measured with IC50 ’s of 0.5 ␮M and for
BChE with 42.58 ␮M. Interaction with AChE readily
cleaved the carbamoyl moity to release the chelator
readily forming complexes with FeSO4 and CuSO4 .
The prochelator is nontoxic to human SH-SY5Y cells
at 25 or 50 ␮M. A recent review described the field in
great detail [478].
Novel indanone derivatives were designed as AChE
inhibitors and metal-chelating agents [479].
2.1.1.11. Dual AChE inhibitors and N-methyl-Daspartic acid receptor channel blockers. Carbacrine
(University of Bologna, Fig. 9), a potent AChE
inhibitor (IC50 = 2.15 nM), and weak inhibitor of
BChE (IC50 = 296 nM), blocked AChE-induced A␤
aggregation to 58% at 100 ␮M and A␤ selfaggregation to 36% at 50 ␮M and inhibited NMDA
receptors with an IC50 of 0.74 ␮M. It is a noncompetitive open-channel blocker. In the ORAC test carbacrine
was a good antioxidant (IC50 = 0.07 ␮M), more potent
than trolox [480].
University of Jena researchers presented bivalent
␤-carbolines as dual AChE inhibitors and NMDA
receptor blockers such as compound 22b (Fig. 9):
IC50 = 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 ␮M
for the NMDA receptor, respectively [481].
Bis(7)-tacrine (Mayo Foundation, Fig. 2, see section 2.1.1.5. Dual AChE inhibitors and calcium
channel blockers) inhibited NMDA receptors with an
IC50 of 763 nM [431].
2.1.1.12. Dual AChE inhibitors & platelet activating factor antagonists. PMS-777 (University of
Paris 7-Denis Diderot and Shanghai Jiao Tong
University; Fig. 10), synthesized in 1996 [482,
483], is a tetrahydrofuran derivative, which inhibited
AChE (IC50 = 2.48 ␮M), BChE (IC50 = 4.47 ␮M), and
acted as platelet factor antagonist (IC50 = 12.5 ␮M)
[484–490]. It inhibited A␤-induced human neuroblastoma SH-SY5Y cell apoptosis in a concentration
dependent manner. It decreased reactive oxygen
species up to 32%, NO production up to 5 times,
and TNF␣ release by 33% (Thomson Reuters Pharma,
update of June 20, 2012).
562
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 9. Dual acetylcholinesterase inhibitors and NMDA receptor blocker.
PMS-1339 (University of Paris 7-Denis Diderot
and Shanghai Jiao Tong University; Fig. 10) is a
novel piperazine derivative, which inhibited AChE
(IC50 = 4.4 ␮M) and BChE (IC50 = 1.09 ␮M), A␤
aggregation (recombinant human AChE-induced:
IC50 = 45.1 ␮M), and acted as platelet factor antagonist (IC50 = 332 nM) [491] (Thomson Reuters Pharma,
update of June 20, 2012).
2.1.1.13. Dual AChE and serotonin transporter
inhibitors. RS-1259 (BGC-20-1259; BRG under
license from Daiichi Sankyo; Fig. 10) is a dual inhibitor
of AChE (IC50 = 101 nM) and of the serotonin transporter (IC50 = 42 nM). It significantly ameliorated the
age-related short-term memory impairment at a dose of
1 mg/kg in rats 24-25 months of age [492]. At 2 mg/kg
RS-1259 was also effective in recovering from memory
deficits. For the design, synthesis and structure-activity
relationships see [493–495]. Its development was terminated.
2.1.1.14. Dual AChE and sigma receptor inhibitors.
SP-04 (Samaritan Pharmaceuticals; Fig. 10) is an
inhibitor of AChE and of sigma-1 receptors. For synthesis and biological evaluation, see [496] (Thomson
Reuters Pharma, update of March 23, 2011).
The development of igmesine (JO-1784; Jouveinal,
now Pfizer) was terminated. See Part 1, Chapter 1.28,
Drugs interacting with Sigma receptors.
2.2. Drugs interacting with alpha-secretase
␣-Secretase cleaves A␤PP at the Lys16-Leu17
bond within the A␤ sequence to generate the soluble N-terminal A␤PP fragment (sA␤PP␣) and the
membrane bound CTF83 (carboxy-terminal fragment
of 83 residues in length) thus precluding the formation and subsequent deposition of A␤. The activation
of the ␣-secretase processing of A␤PP as a therapeutic approach in AD was reviewed [497–501]. The
activation of ␣-secretase is controlled by the protein phosphorylation signal transduction pathway of
protein kinase C (PKC). A review on ␣-, ␤-, and
␥-secretases in AD was published [502].
Etazolate (EHT-0202; SQ-20009; Exonhit; Fig. 10)
is an orally active phosphodiesterase (PDE) 4 inhibitor
and anxiolytic GABAA receptor modulator. Etazolate
dose-dependently increased the secreted levels of nonamyloidogenic sA␤PP␣ in cortical neurons of rats
thus shifting A␤PP processing toward the ␣-secretase
pathway [503]. Etazolate improved the memory performance in aged rats [504]. The results of the first Phase
II 3-month, randomized, placebo-controlled, double-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
563
Fig. 10. Two dual acetylcholinesterase & platelet-activating factor, one acetylcholinesterase & serotonin transporter, one acetylcholinesterase
and sigma-1 receptor inhibitor(s) and an ␣-secretase activator.
blind study in AD patients were reported [505]. The
drug was shown to be safe and well tolerated (Thomson
Reuters Pharma, update of September 13, 2011).
Bryostatin-1 (Blanchette Rockefeller Neurosciences Institute) is a naturally occurring PKC
activator isolated from the Californian marine bryozoan Bugula neritina. Bryostatin-1 increased brain
levels of sA␤PP␣ and reduced brain A␤40 levels,
which may be explained by activation of ␣-secretase
[499, 506]. In February 2012, the Institute was
preparing to initiate clinical trials in neurological
disorders. Chemistry and biology of bryostatins was
reviewed [507] (Thomson Reuters Pharma, update
of February 24, 2012). See also section 2.35. Drugs
interacting with Protein Kinase C.
NP-17, NP-21, NPM-01, NPM-05B1, and NPM05B2 (Noscira) are orally available ␣-secretase
activators of marine origin for the potential treatment
of AD (Thomson Reuters Pharma, updates of July 27,
2011). The structures were not communicated.
Many compounds shifted A␤PP processing toward
the ␣-secretase pathway in in vitro experiments, such
as muscarinic acetylcholine receptor agonists, MAOB inhibitors, statins, non-steroidal anti-inflammatory
drugs (NSAIDs), neuropeptides such as PACAP,
estrogen, and others [499]. However, the benefit for
AD patients in clinical trials was (so far) disappointing.
2.3. Drugs interacting with beta secretase
In the amyloidogenic pathway, A␤PP is first
cleaved by ␤-secretase (BACE1, EC 3.4.23.46 [508,
509]) between residue methionine 671 and aspartic
acid 672 to release a 100 kDa N-terminal fragment
sA␤PP and a 12 kDa membrane bound CFT99,
which is subsequently cleaved by ␥-secretase within
the transmembrane region to form C-terminal A␤
peptides ranging from 38 to 43 residues. ␤-secretase
was cloned simultaneously by five groups in 1999 and
early 2000: at Amgen [510, 511]; at Elan [512], at
Pharmacia & Upjohn, now Pfizer [513], at GSK [514],
and at the Oklahoma Medical Research Foundation
[515]. It is a 501 amino acid protein with two active
564
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
site motifs at amino acids 93-96 and 289-292. It
is structurally related to renin, cathepsins D and E,
pepsinogens A and C, and the retroviral aspartic
proteases [516, 517]. The ␤-secretase-1 gene was
described [518] as was the cell biology, regulation,
and inhibition of ␤-secretase [519]. For the enzymatic
activities of ␤-secretase-1 and ␤-secretase-2 (BACE2;
EC 3.4.23.45) in AD, see [520]. ␤-secretase-1 is
also required for myelination and correct bundling of
axons by Schwann cells [521, 522].
An X-ray crystal structure of ␤-secretase-1 bound
to the octapeptidic inhibitor OM99-2 was published
[523, 524]. Apo and inhibitor complex structures of
␤-secretase-1 at the resolution of 1.75 Å were determined [525]. X-ray crystal structures of ␤-secretase-1
bound to a macrocyclic peptidomimetic [526] and to
a spiropiperidine iminohydantoin were communicated
[527], as was the crystal structure of an active form of
␤-secretase-1 [528].
␤-secretase-1 knockout mice are healthy despite
lacking the primary ␤-secretase activity in the brain
[529, 530]. ␤-secretase-1 null mice are rescued from
A␤-dependent hippocampal memory deficits [531].
A rare gene mutation in the A␤PP was identified
in an Icelandic population by scientists of deCode
genetics, which protects against AD and age-related
cognitive decline. This A673T mutation is directly
adjacent to the cleavage site of ␤-secretase (methionine
671 and aspartic acid 672) [532]. For a commentary,
see [533].
In view of the importance of the amyloid hypothesis
for AD, it is not surprising that many pharmaceutical companies embarked on medicinal chemistry
programs to discover ␤-secretase inhibitors (in alphabetical order): Actelion, Allosterix, ALSP, Amgen,
Archer Pharmaceuticals, Astellas, Astex Therapeutics,
AstraZeneca, BACE Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CoMentis (company of
Prof. Jordan Tang), Critical Outcome Technologies, De
Novo Pharmaceuticals, DuPont Pharma, Elan, Envoy
Therapeutics, Evotec, Genetics Company, GlaxoSmithKline, IntelliHep, JADO Technologies, Johnson
& Johnson, Kyoto University, LG Life Sciences,
Ligand Pharmaceuticals, Lilly, Locus Pharmaceuticals, Medivir, Merck, NasVax, Noscira, Novartis,
Pfizer, ProMediTech, Roche, Samada Research, sanofi,
Schering-Plough, Senex Biotechnology, Shionogi,
Sibia, Sunesis Pharmaceuticals, Takeda, Trans-Tech
Pharma, Vertex Pharma, Vitae Pharmaceuticals, and
Wyeth. In addition, there are numerous excellent
papers by competent synthetic organic chemists and
molecular modelers working at universities. The prob-
lems of ␤-secretase inhibitors are mostly due to their
peptidomimetic structures displaying high molecular
weight, high polar surface area, low oral bioavailability, metabolic instability, low blood brain barrier
penetration, and susceptibility to P-glycoprotein transport out of the brain.
There are many interesting reviews on the pharmacology and medicinal chemistry of ␤-secretase
inhibitors (in chronological order): 2001: [534–536]
2002: [537–543], 2003: [544–547], 2004: [548–550],
2005: [551, 552], 2006: [553–557], 2007: [558–560],
2008: [517, 561–563], 2009: [508, 564–569], 2010:
[570–574], 2011: [575–578], 2012: [579–581].
LY-2886721 (Eli Lilly) was in two Phase I clinical trials since June 2010 (n = 50) and December 2010
(n = 60) in the US. The studies were completed in
October 2010 and in April 2011, respectively. In April
2012 a randomized, double-blind, placebo-controlled,
Phase I/II study (NCT01561430) was initiated in
patients with mild cognitive impairment due to AD
(expected n = 129) in the US and is scheduled to complete in December 2013. For medicinal chemistry, see
[582–586] (Thomson Reuters Pharma, update of July
27, 2012). The structure was not communicated.
CTS-21166 (ASP-1702, ATG-Z1; Astellas Pharma
and CoMentis) is a ␤-secretase-1 inhibitor in Phase I
clinical trials since June 2007. In 48 volunteers, the
drug was safe and well tolerated (Thomson Reuters
Pharma, update of July 10, 2012). The structure was
not communicated.
E-2609 (Eisai) is a ␤-secretase inhibitor in Phase
I clinical trials since December 2010 in the US in
healthy young and elderly volunteers (n = 48). The
trial was completed in May 2012. Multiple-ascending
oral doses of E-2609 (25 to 400 mg for 14 days)
were studied at a single site in the US in this ongoing
trial in healthy human volunteers of 50 to 85 years
of age (both genders). The drug was safe and well
tolerated with minor adverse effects. Reductions of
A␤ in CSF and plasma were demonstrated following
both single and repeated administrations (Thomson
Reuters Pharma, update of August 07, 2012). The
structure was not communicated.
HPP-854 (TTP-854; High Point Pharmaceuticals,
a spin-out from TransTech Pharma) is a ␤-secretase
inhibitor in Phase I clinical trials since November 2009
(Thomson Reuters Pharma, update of April 5, 2012).
The structure was not communicated.
MK-8931 (SCH-900931; Schering-Plough, now
Merck; Fig. 11) is an inhibitor of ␤-secretase in
Phase I clinical trials since October 2009 (n = 40).
In April 2012 data were presented from a two-part,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 11. Beta-secretase inhibitors.
565
566
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
randomized, double-blind, placebo-controlled single
rising-dose study (n = 40). Single doses of MK-8931
from 2.5 to 550 mg were well-tolerated [587]. For
medicinal chemistry, see [548, 588–593] (Thomson
Reuters Pharma, update of August 13, 2012).
For further documentation on the impressive
␤-secretase-1 inhibitor research program ongoing at
Merck see (in chronological order): [594–621 [2]].
At the occasion of the 244th ACS meeting in
Philadelphia Merck presented a bicyclic iminoheterocycle compound (Fig. 11) with an optimized
thiadiazine subunit with high affinity for ␤-secretase.
RG-7129 (Roche from a research collaboration with
Siena Biotech) is a small molecule ␤-secretase (BACE)
inhibitor in Phase I development since September
2011 (Thomson Reuters Pharma, update of August 8,
2012). The structure was not communicated. See also
the interesting papers [621, 622].
Several ␤-secretase inhibitors of known structure are
in preclinical evaluation (in alphabetical order):
Amgen (presumably AC-3; AMG-0683; Fig. 11)
investigated series of 2-aminoquinolines and 2aminopyridines as ␤-secretase-1 inhibitors [623].
Hydroxy-ethylamine containing ␤-secretase inhibitors
were described very recently [624, 625] (Thomson
Reuters Pharma, update of July 31, 2012).
AZ-13 (Astex Pharmaceuticals and AstraZeneca;
Fig. 11) at 50, 75, 100, or 300 mmol/kg achieved a
concentration-dependent decrease in A␤40 , A␤42 , and
sA␤PP levels in brain and plasma of C57BL/6 mice.
For medicinal chemistry, see [626–629] (Thomson
Reuters Pharma, update of August 2, 2012).
Bristol-Myers Squibb (Fig. 11) is investigating a
series of 7-aza-indole compounds with IC50 values of
10 nM against BACE-1 and 800 nM against BACE2. For medicinal chemistry, see [630–635] (Thomson
Reuters Pharma, update of August 8, 2011).
Elan (Fig. 11) presented data on hydroxyethylamine
␤-secretase-1 inhibitors with IC50 values against
␤-secretase-1 of 12 nM and an ED50 value of 2.1 nM
in a HEK-293 cellular assay. For medicinal chemistry,
see [636–643] (Thomson Reuters Pharma, update of
August 13, 2012).
Johnson & Johnson (presumably JNJ-715754,
Fig. 11) is evaluating compounds from a series
of aminopiperazines with an IC50 of 40 nM in a
␤-secretase-1 enzymatic assay, of 28 nM for hA␤42 ,
and 25 nM for hA␤Total. Many medicinal chemistry papers were communicated [644–649] (Thomson
Reuters Pharma, update of January 18, 2012).
KMI-008, KMI-358, KMI-370, KMI-420,
KMI-429, KMI-574, KMI-1027, and KMI-1303
(Kyoto Pharmaceutical University) are potent BACE1
inhibitors [650–665]. KMI-429 (Fig. 12) is a
␤-secretase 1 inhibitor with enhanced cell membrane
permeability (IC50 = 3.9 nM). KMI-574 (Fig. 12)
is a ␤-secretase inhibitor produced by substituting
the side chain of KMI-429 with a bioequivalent
material to enhance blood-brain barrier permeability
(IC50 = 5.6 nM). KMI-1027 (Fig. 12) is a low molecular weight ␤-secretase inhibitor with enhanced in vivo
enzyme stability and blood-brain barrier permeability
(IC50 = 50 nM). KMI-1303 (Fig. 12) is a ␤-secretase
1 inhibitor with higher affinity for active site pockets
(IC50 = 9 nM). The structures were obtained from
the Wako Online Catalog, Research for Alzheimer’s
Disease, edition November 2011.
L-655240 (Merck, Fig. 12) is a thromboxane A2
antagonist, which was re-discovered as a BACE1
inhibitor with IC50 of 4.47 ␮M by Chinese authors
[666].
Novartis (Fig. 11) investigated a series of cyclic
sulfoxide hydroxyethylamine ␤-secretase-1 inhibitors.
The compound reduced CSF and brain A␤40 levels in
a dose-dependent manner and showed good efficacy
at a 10 fold lower dose, when co-administered with
the CYP3A4 inhibitor ritonavir in various animal models. For medicinal chemistry, see [667–671]. (Thomson
Reuters Pharma, update of July 5, 2011).
TAK-070 (University of Tokyo under license from
Takeda) is a ␤-secretase and A␤ aggregation inhibitor
(Thomson Reuters Pharma, update of June 8, 2012).
The structure was not communicated.
WAY-258131 (Wyeth, now Pfizer; Fig. 11) inhibited
␤-secretase-1 with an IC50 value of 10 nM and reduced
A␤40 with an IC50 value of 20 nM. For medicinal
chemistry, see [672–689] (Thomson Reuters Pharma,
update of August 15, 2012).
Several companies have ␤-secretase-1 inhibitors
in preclinical development, whose structures were
not communicated (in alphabetical order): Allosterix,
BACE Therapeutics, Boehringer Ingelheim, Envoy
Therapeutics [690], Evotec [691, 692], Il Dong
Pharma (Seoul), IntelliHep (heparinoid ␤-secretase
inhibitors), LG Life Sciences [693], ProMediTech,
Samada Research, Vitae Pharmaceuticals in collaboration with Boehringer Ingelheim and the Technical
University of Munich [694, 695].
A dual ␤-secretase-1 inhibitor and metal chelator
was described [696].
Dual ␣7 nicotinic acetylcholine receptor activators and ␤-secretase-1 inhibitors are investigated in
a program at the University of Maryland (Thomson
Reuters Pharma, update of February 24, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 12. Beta-secretase inhibitors II.
567
568
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
JADO Technologies synthesized a membraneanchored version of a ␤-secretase transition-state
inhibitor by linking it to a sterol moiety. This inhibitor
reduced enzyme activity much more efficiently than
did the free inhibitor in cultures cells and in vivo [697].
BBS-1 BACE inhibitor mAb vaccine (NasVax
under license from Ramot at Tel Aviv University) is
investigating a vaccine based on its lead mAb candidate
BBS-1 (blocking ␤-site-1), which inhibits the ability
of ␤-secretase-1 to cleave A␤PP (Thomson Reuters
Pharma, update of July 30, 2011).
Antibodies directed against the ␤-secretase cleavage site of A␤PP were described [698, 699].
Brain-targeted BACE1 antibody (Genentech,
Roche Holding) is a bi-specific antibody against
␤-secretase-1 and the transferrin receptor to allow
transcytosis across the blood-brain barrier [700, 701]
(Thomson Reuters Pharma, update of May 14, 2012).
This technique was pioneered by W. M. Pardridge of
UCLA [702–708].
Excellent papers on ␤-secretase-1 inhibitors from
universities were presented (in alphabetical order of
their location): Mahidol University Bangkok [709,
710], University of Darmstadt [711], TU Dresden
[712], University of Duisburg-Essen [713], Gwangju
Institute of Science and Technology Korea [714],
Linköping University [715]; University of Liverpool
[716, 717], University of Marseille [718], Max-PlanckInstitut für Biochemie Martinsried [719], University
of Montréal [720–722], Technical University Munich
[695], Peking University [723], University of Pisa
[724–726], Purdue University [536, 559, 561, 727,
728], Sapienza University Rome [729], Shanghai Institute of Materia Medica [730, 731], Shujitsu University
[732], Stockholm University [733–735], University
of South Florida Tampa [736], University of Tokyo
[665], SISSA-ISAS Trieste [737], CNRS Valbonne
[738, 739], and Uppsala University [740–743].
Excellent papers on theoretical calculations on
␤-secretase-1 inhibitors were presented (in chronological order) 2001: [744], 2003: [644], 2004: [645,
646, 745], 2005: [746, 747], 2006: [748–751], 2007:
[752–754], 2008: [755, 756], 2009: [757, 758], 2010:
[759–765], 2011: [766–771], 2012: [772–778].
Several companies or institutions seem to have abandoned the search for novel ␤-secretase-1 inhibitors,
such as Actelion, De Novo, the Genetics Co (CallistoGen), Ligand, Locus Pharmaceuticals, Medivir [779],
Noscira, and Plexxikon.
The development of allosteric peptide BACE-1
inhibitors (Allosterix), of ARC-050 (Archer Pharmaceuticals), AZD-3839 (AstraZeneca [780, 781]),
BACE inhibitors (BACE Therapeutics, Evotec,
Samada Research, and ProMediTech/LG Life Sciences), GRL-8234 (Oklahoma Medical Research
Foundation [782]), GSK-188909 (GSK [783–791]),
LY-2811376 (Lilly [792]), SIB-1281 (Sibia), of TAK070 (Takeda [793, 794]), and of TC-1 (Merck under
license from Sunesis [795, 796]) was terminated.
2.4. Drugs interacting with gamma-secretase
␥-secretase is an aspartyl protease that cleaves
its substrates within the transmembrane region in a
process termed regulated-intramembrane-proteolysis
(RIP). The enzyme consists of four protein components: presenilin 1 or 2, which contains the catalytic
domain, nicastrin, Aph-1 (anterior pharynx-1), and
Pen-2 (presenilin enhancer-2) in a 1 : 1:1 : 1 ratio [797].
It is hypothesized that the free N-terminus of a ␥secretase substrate first binds to the ectodomain of
nicastrin (a 709 amino acid type 1 membrane glycoprotein), which may facilitate its interaction with the
docking site on presenilin followed by relocation to the
active site on presenilin, where it is cleaved [798–812].
␥-secretase cleaves A␤PP transmembrane domain in a
progressive stepwise manner at the ␧, ζ, and ␥-sites,
resulting in A␤ species of varying length. This stepwise cleavage may occur via two different routes. They
initiate with the formation of A␤49 and A␤48 and
then proceed via the cleavage at approximately every
three residues, i.e., every helical turn of the substrate.
The two product lines are ␧49-ζ46-␥43-␥40 and ␧48ζ45-␥42. Further cleavage will subsequently generate
the other isoforms A␤39 , A␤38 , and A␤37 , of which
A␤38 results from the product line containing A␤42
[813–816]. The mechanism of ␥-secretase dysfunction
in familial AD was addressed [817].
␥-secretase also cleaves other protein substrates,
e.g., Notch, Jagged, and Nectin 1␣ [818–821].
␥-secretase cleavage of Notch leads to the release of the
smaller cytosolic fragment NICD (Notch intracellular
domain) important in signal transduction pathways. ␥secretase inhibitors that are not Notch-sparing may
cause severe gastrointestinal toxicity and interfere
with the maturation of B- and T-lymphocytes in mice
[822–827]). Note that A␤PP interacts with Notch
receptors [828].
The first proof that ␥-secretase inhibitors reduced
A␤ peptide levels in the brain was published already
in 2001 by Elan scientists [829].
In view of the importance of the amyloid hypothesis
for AD, it is not surprising that many pharmaceutical companies embarked on medicinal chemistry
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
programs to discover ␥-secretase inhibitors and
modulators (in alphabetical order): Archer Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Cellzome,
Eisai, Elan, EnVivo Pharmaceuticals, Harvard Medical School, Intra-Cellular Therapies, Janssen, Lilly,
Merck, Myriad Genetics, NeuroGenetic Pharmaceuticals, Ortho-McNeill, Pfizer, Roche, TorreyPinesTherapeutics and Wyeth (now Pfizer). There are many highly
interesting publications on medicinal chemistry and
pharmacology of ␥-secretase inhibitors and modulators reviewed (in chronological order) 2002: [539,
830–834]; 2003: [835]; 2004: [836, 837]; 2005: [838,
839]; 2006: [556, 557, 840–843]; 2007: [819]; 2008:
[844]; 2009: [809, 845–847]; 2010: [848, 849]; 2011:
[577, 850]; 2012: [851, 852].
A review on the molecular modeling and the design
of ␥-secretase inhibitors was presented [607].
Many excellent reviews on the therapeutic potential of ␥-secretase inhibitors and modulators were
published [850, 853–863].
2.4.1. Gamma-secretase inhibitors
Avagacestat (BMS-708163; Bristol-Myers Squibb;
Fig. 13) is an orally active ␥-secretase inhibitor that
selectively inhibited A␤ production. A Phase II trial
in 200 AD patients was initiated in February 2009;
a second Phase II trial in 270 prodromal AD (mild
cognitive impairment) patients over a period of 104
weeks was initiated in May 2009. First reports on the
tolerability profile, pharmacokinetic parameter, and
pharmacodynamics markers were published [864–866
[3]]. A sensitive and selective LC-MS/MS method for
determination of avagacestat in plasma and CSF was
presented [866]. For medicinal chemistry and pharmacology, see [867, 878] (Thomson Reuters Pharma,
update of August 10, 2012).
NIC5-15 (Humanetics under license from the
Mount Sinai School of Medicine, Fig. 13) is the natural
product D-pinitol, which inhibits the formation of A␤
plaques and inhibits ␥-secretase. In July 2009 encouraging Phase IIa data of the study NCT00470418 were
reported (Thomson Reuters Pharma, update of January
19, 2012).
E-2212 (Eisai), a ␥-secretase inhibitor, is in Phase
I clinical evaluation since January 2010 (n = 91). The
structure of E-2212 was not communicated. E-2212
replaces the abandoned ␥-secretase modulator E-2012
(Thomson Reuters Pharma, update of March 15, 2011).
(−)-GSI-1 (L-685,458; SCH-900229; Merck;
Fig. 13) has an EC50 value of 15 mg/kg in a rat model
and displayed excellent oral pharmacokinetics. GSI-1
lowered A␤40 plasma concentration. By August 2011,
569
Phase I trials had begun. For the extensive medicinal
chemistry see [879–902] (Thomson Reuters Pharma,
update of May 04, 2012).
Several ␥-secretase inhibitors are currently in preclinical evaluation (in alphabetical order):
Harvard Medical School scientists are investigating a series of Notch-sparing ␥-secretase inhibitors for
the potential treatment of AD (one structure shown
in Fig. 13). One of the compounds (AD-1068) has an
IC50 value of 9 nM against A␤42 and an IC50 value of
1.8 ␮M for Notch. For medicinal chemistry (early work
was performed in part at the University of Tennessee),
see [903–911]. An excellent review was published in
2010 [848]. It appears that the development was terminated recently (Thomson Reuters Pharma, update of
June 25, 2012).
MRK-560 (SCH-1375975; Schering-Plough, now
Merck; Fig. 13) reduced A␤ plaque deposition without evidence of notch-related pathology in the Tg2576
mouse [912–915]. For medicinal chemistry, see [885,
916–919, 895, 896, 920–927] (Thomson Reuters
Pharma, update of November 24, 2011).
NGP-555 (NeuroGenetic Pharmaceuticals, Fig. 14)
has an IC50 for A␤ of 8.3 nM. It reduced levels of
A␤42 in brain and plasma at doses up to 100 mg/kg p.o.
Chronic treatment with 50 mg/kg for 7 months significantly reduced the percentage area of plaques in mouse
brains. There was no evidence of Notch-mediated GI
toxicity [928]. A potential follow-up compound may be
NGP-328, whose structure was not disclosed (Thomson Reuters Pharma, update of June 4, 2012).
Pepscan Therapeutics is investigating a series of
peptide-based ␥-secretase inhibitors for the potential
treatment of AD (Thomson Reuters Pharma, update of
April 1, 2011). The structures were not communicated.
Pfizer (Fig. 14) presented a novel ␥-secretase
inhibitor containing a bicyclo-[1.1.1]-pentanyl moiety
with an IC50 of 0.178 nM being equipotent to avagacestat (IC50 = 0.196 nM) [929]. For additional medicinal
chemistry papers from Pfizer, see [930–935] (Thomson
Reuters Pharma, update of July 30, 2012).
RO-02 (Roche; Fig. 14) inhibited enzyme activity with an A␤42 inhibition IC50 value of 500 nM.
For medicinal chemistry, see [936] (Thomson Reuters
Pharma, update of July 20, 2011).
Large ␥-secretase inhibitor research programs were
also ongoing at Amgen [937] and at Elan, see
[938–947].
Excellent papers on ␥-secretase inhibitors from universities were presented (in chronological order) 2001:
[948, 949]; 2004: [950, 951]; 2005: [952]; 2006: [953,
954]; 2009: [955, 956]; 2010: [957]; 2012: [958, 959].
570
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 13. ␥-secretase inhibitors.
Excellent papers on theoretical calculations on
␥-secretase inhibitors have been presented (in chronological order) [960–967].
Critical Outcome Technologies is investigating
orally available, dual ␤- and ␥- secretase inhibitors
(Thomson Reuters Pharma, update of June 24,
2011).
The development of several ␥-secretase inhibitors
was terminated, of ARC-069 (Archer Pharmaceuticals, Roskamp Institute), begacestat (GSI-953;
WAY-210953; PF-5212362; Wyeth, now Pfizer [809,
968–974]), BMS-299897 (Bristol-Myers Squibb;
[975–978]), BMS-433796 (Bristol-Myers Squibb
[869, 979]), E-2012 (Eisai), ELND-006 and ELND007 (both Elan [944–946, 980, 981]; GSI-136 (Wyeth,
now Pfizer [982]), MK-0752 (Merck; in Phase II for the
treatment of cancer, but terminated for the indication
of AD [983]); PF-03084014 (Pfizer; in Phase I for the
treatment of cancer, but terminated for the indication
of AD [984–987]), RO-4929097 (RG-4733; Roche,
for the indication breast cancer [988–993]), semagacestat (LY-450,139; Eli Lilly [931, 932, 994–1010])
and of SR-973 (DuPont/Scios, now Bristol-Myers
Squibb).
2.4.2. Gamma-secretase modulators
A ␥-secretase modulator interacts with allosteric
binding sites at the protease complex shifting the proteolytic processing of A␤PP toward higher production
of shorter A␤ species such as A␤38 at the expense of
the highly toxic A␤42 isoform. Impairment of Notch
processing and signaling was not observed [1011].
Reviews on ␥-secretase modulators were presented (in
chronological order) 2005: [1012]; 2006: [556, 557,
1013]; 2007: [1014, 1015]; 2008: [833, 1016–1019];
2010: [821]; 2011: [1020, 1021]; 2012: [1022–1024].
Tarenflurbil (MPC-7869; (R)-flurbiprofen, Flurizan, Myriad Genetics, Loma Linda University;
Fig. 14) is a COX inhibitor and ␥-secretase modulator that selectively reduced the levels of A␤42 in
vivo [1025, 1026]). The IC50 values for the inhibition of COX-1 are 44 ␮M, of COX-2 : 123 ␮M, and of
A␤42 : 280 ␮M [1027]. Chronic administration of Rflurbiprofen attenuated learning impairments in transgenic A␤PPswe mice [1028]. Tarenflurbil upregulated
nerve growth factor and brain-derived neurotrophic
factor protecting both human neuroblastoma cell lines
and primary neurons from cytotoxicity associated with
exposure to A␤42 or hydrogen peroxide [1029].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
571
Fig. 14. ␥-secretase inhibitors and modulators.
Tarenflurbil was tested in a Phase II study in 210
patients with doses of 400 mg and 800 mg twice per
day or placebo for 12 months. Patients with mild AD in
the 800 mg tarenflurbil group had lower rates of decline
than those in the placebo group concerning activities
of daily living. In patients with moderate AD 800 mg
tarenflurbil twice a day had no significant effects on
ADCS-ADL and ADAS-cog [1030].
Tarenflurbil was tested in a Phase III study in 1,684
patients, of which 1,046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary
outcomes for ADCS-ADL and for ADAS-cog [1031];
for commentaries see [1032–1034] (Thomson Reuters
Pharma, update of August 24, 2012).
With the termination of the development of
tarenflurbil, the NO-releasing flurbiprofen derivative
HCT-1026 (NicOx) was also stopped.
CHF-5074 (Chiesi Farmaceutici; Fig. 14) showed a
concentration dependent inhibitory activity on A␤42
secretion (IC50 = 40 ␮M). At 300 ␮M, an inhibitory
effect was detected on COX-1 (–40%), but not on
COX-2 [1035]. It is devoid of Notch-interfering activities in vitro [1036]. Treatment of 6 months old hA␤PP
transgenic mice for 6 months significantly reduced
the number of plaques in cortex and hippocampus,
whereas ibuprofen did not reduce A␤ burden [1037].
CHF-5074 treatment of Tg2576 mice from 6 to 15
months of age resulted in a significant attenuation of
the neurogenesis impairment in hippocampus [859,
1038]. For the reduction of the accumulation of hyperphosphorylated tau, see [1039], for the restoration
of hippocampal plasticity in Tg2576 mice [1040]
and for the effects in a mouse model of scrapie
[1041].
CHF-5074 was tested in a double-blind, placebocontrolled Phase I ascending oral dose study in 48
healthy males with 200, 400, and 600 mg/day for 14
days (n = 12 each per dose level and 12 receiving
placebo). The drug was well tolerated. In March 2011,
a Phase II trial was initiated in the US and in Italy
(n = 96). Trial completion is expected for July 2012
(Thomson Reuters Pharma, update of July 23, 2012).
EVP-0962 (EnVivo Pharmaceuticals) is a ␥secretase modulator in Phase I clinical evaluation since
June 2011 in healthy volunteers. By June 2012, the
Phase I trial was completed (Thomson Reuters Pharma,
update of August 14, 2012). Its structure was not communicated.
572
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Several ␥-secretase modulators are currently in preclinical evaluation (in alphabetical order):
Amgen (Fig. 15) presented preclinical data on a
novel ␥-secretase modulator at the occasion of the
41st SFN Meeting in Washington in November 2011
(Thomson Reuters Pharma, update of December 6,
2011).
AZ-4800 (AstraZeneca; Fig. 15) at 75, 150, and
300 ␮mol/kg caused a dose dependent decrease of
brain A␤42 1.5 hours after administration to C57
mice (Thomson Reuters Pharma, update of April 1,
2011). For medicinal chemistry, see [1042, 1043].
AstraZeneca scientists described the detailed pharmacological evaluation of the ␥-secretase modulators
AZ3303 and AZ1136 (both Fig. 16) [1044, 1045]. The
second-generation ␥-secretase modulators have different modes of action regarding Notch processing [1046]
(Thomson Reuters Pharma, update of July 4, 2012).
BIIB-042 (Biogen Idec; Fig. 15) is a ␥-secretase
modulator, which significantly reduced brain A␤42 levels in CF-1 mice and in Fisher rats and plasma A␤42
levels in cynomolgus monkeys. For medicinal chemistry, see [1047, 1048] (Thomson Reuters Pharma,
update of March 27, 2012).
GSM-2 (Merck UK [1049], Fig. 15), as was investigated by scientists of Astellas [1050], significantly
ameliorated memory deficits in Tg2576 mice and did
not affect normal cognition in wild-type mice. In contrast ␥-secretase inhibitors avagacestat (BMS-708163)
and semagacestat (LY-450139) on subchronic dosing
impaired normal cognition in 3 month old Tg2576
mice.
GSM-10h (GSK, Fig. 15) is an orally
active piperidine-derived ␥-secretase modulator
[1051–1054]. GSK is also investigating ␥-secretase
modulators derived from pyridazines (Fig. 15 [1055])
and from pyridines (Fig. 15) [1056] (Thomson
Reuters Pharma, update of January 13, 2012).
Janssen described a novel series of bicyclic heterocycles as potent ␥-secretase modulators [1057].
Merck (Fig. 16) is investigating ␥-secretase modulators with fused 5,6-bicyclic heterocycles. The best
compound had an IC50 of 122 nM for the inhibition
of A␤42 and exhibited good selectivity over overall
␥-secretase inhibition (IC50 ratio of 38 fold). In rats,
the compound reduced A␤42 in the CSF by 26%
after 3 hours at 30 mg/kg p.o. Medicinal chemistry
was described [1058–1063]. Important mechanistic
insights were contributed [1064] (Thomson Reuters
Pharma, update of August 15, 2012).
Merck (Fig. 16) presented a new series of triazole
analogues, which inhibited A␤42 and A␤40 with IC50
values of 0.2 and 2.06 ␮M, respectively, and showed
a hERG interaction of IC50 > 10 ␮M [1065, 1066].
In a third series, Merck scientists presented pyridone
and pyridazone heterocycles as ␥-secretase modulators
[1067].
Pfizer medicinal chemists presented novel dihydrobenzofuran amides as orally bioavailable, centrally
active ␥-secretase modulators [1068] (Thomson
Reuters Pharma, update of July 30, 2012).
Roche presented novel ␥-secretase modulators at the
occasion of the Alzheimer’s Association International
Conference in Paris, France, July 16–21, 2011. One
compound (Fig. 16) had an A␤42 EC50 value of 0.1 ␮M
and demonstrated dose-dependent efficacy in transgenic A␤PPswe mice. CSF A␤42 levels were reduced
in non-transgenic rats for longer than 8 hours. A good
pharmacokinetic profile was seen (Thomson Reuters
Pharma, update of July 27, 2012).
SPI-014, SPI-1802, SPI-1810, and SPI-1865
(Satori Pharmaceuticals, Figure 16) are ␥-secretase
modulators reducing the levels of A␤42 without altering total A␤ levels in cell lines and in animal models
of AD (Thomson Reuters Pharma, update of July 31,
2012). The structures were not communicated.
TorreyPines Therapeutics presented a novel class of
aminothiazoles as ␥-secretase modulators. Compound
3 (Fig. 16) displayed an IC50 for A␤42 of 5 nM [1069].
Excellent papers on ␥-secretase modulators from
universities were presented from the TU Darmstadt
[1070–1074], the University of Duesseldorf [1075],
Emory University [1076], from the Mayo Clinic
[1077], the Memorial Sloan-Kettering Cancer Center
[1078–1080], the University of Munich [1081, 1082],
and the University of Tokyo [1083].
Excellent papers on theoretical calculations on
␥-secretase modulators were presented from the University of Duesseldorf [1084], the Massachusetts
General Hospital [1085–1087], and Vanderbilt University [1088].
Dual modulators of ␥-secretase and peroxisome
proliferator-activated receptor ␥ (PPAR␥) were
presented to produce compounds with IC50 (A␤42 ) of
5.1 ␮M and EC50 (PPAR␥) of 6.6 ␮M [1089, 1090].
The development of JNJ-4018677 and JNJ42601572 (Janssen, formerly Ortho-McNeil Pharmaceuticals under license from Cellzome) [1091] was
discontinued.
2.4.3. Inhibitors of gamma-secretase activating
protein
␥-secretase activating protein (GSAP) interacts
both with ␥-secretase and its substrate, the A␤PP
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 15. ␥-secretase modulators.
573
574
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 16. ␥-secretase modulators and a Notch pathway inhibitor.
carboxy-terminal fragment (A␤PP-CTF). Reducing
GSAP concentrations in cell lines decreased A␤
concentrations, hence GSAP may be a new therapeutic target for AD [1092]. For a commentary, see
[1093]. The immunohistochemical characterization of
␥-secretase activation protein expression in AD brains
was described [1094]; the purification and characterization of human GSAP [1095].
IC-200155 (Intra-Cellular Therapies) is a compound that decreases A␤ levels in the brain by
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
575
Fig. 17. One 11␤ hydroxysteroid dehydrogenase inhibitor, three calpain and one cathepsin B inhibitor(s).
interacting with GSAP (Thomson Reuters Pharma,
update of February 24, 2012). The structure was not
communicated.
2.4.4. Notch pathway inhibitors
AGT-0031 (AxoGlia Therapeutics; Fig. 16) is an
inhibitor of the Notch pathway, which is involved in
astrocyte differentiation and inflammatory activation
for the potential treatment of multiple sclerosis and
AD (Thomson Reuters Pharma, update of February
29, 2012).
2.5. Drugs interacting with beta hexosaminidase
The first report of short-term memory deficits in a
murine model of lysosomal storage diseases including
Sandhoff disease was described [1096].
Amicus Therapeutics is investigating small
molecule pharmacological chaperones that bind to and
activate the lysosomal enzyme beta-hexosaminidase
for the potential oral treatment of AD. These
compounds lowered the levels of GM2 and GM3
gangliosides associated with A␤ aggregation (Thom-
son Reuters Pharma, update of March 28, 2012). No
structures were communicated.
2.6. Drugs interacting with 11 beta
hydroxysteroid dehydrogenase
The topic 11␤-hydroxysteroid dehydrogenase type
1 (11␤-HSD-1), brain atrophy, and cognitive decline
was reviewed [1097, 1098]. 11␤-HSD1 expression was
enhanced in the aged mouse hippocampus and caused
memory impairment [1099]. Enhanced hippocampal
LTP and spatial learning was found in 11␤-HSD1
knockout mice [1100, 1101]. Partial deficiency or
short term inhibition of 11␤-HSD1 improved cognitive
function in aged mice [1102, 1103]). Inhibition of 11␤hydroxysteroid dehydrogenase by carbenoxolone (100
mg three times per day) improved cognitive function
in elderly men [1104].
ABT-384 (Abbott Laboratories) is in a doubleblind safety/efficacy Phase II trial since May 2010 in
patients (n = 260) with mild to moderate AD in the UK.
Despite being safe, well tolerated and tested at doses
associated with full inhibition of brain 11␤-HSD-1
activity, it did not induce symptomatic improvement in
576
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
mild to moderate AD during the 12-week trial period.
Therefore the trial was terminated (Thomson Reuters
Pharma, update of July 18, 2012). The structure of
ABT-384 was not communicated.
KR-1-2 (Korea Research Institute of Chemical
Technology) suppressed cortisol by inhibiting 11␤hydroxysteroid dehydrogenase type 1. The drug is
intended for the treatment of glaucoma and dementia (Thomson Reuters Pharma, update of February 27,
2012).
UE-1961, UE-2811 (Fig. 17) and UE-2343 (Univ.
of Edinburgh in collaboration with Argenta Discovery)
are inhibitors of 11␤-hydroxysteroid dehydrogenase
1 (11␤-HSD1) for the potential treatment of agerelated cognitive disorders, such as memory loss
[1102]. UE-2343 showed cognition enhancement in
aged transgenic Tg2576 mice after one month of treatment in a passive avoidance test and a significant
reduction of their A␤ plaque load (Thomson Reuters
Pharma, update of March 15, 2012). Another class
of 11␤-HSD1 inhibitors, i.e., 1,5-substituted 1H tetrazoles, was described [1105].
2.7. Drugs interacting with calpain
The mechanistic involvement of the calpaincalpastatin system in AD neuropathology was
reviewed [1106]. Calpain inhibitors for the treatment
of AD were discussed [1107, 1108]. Over-activated
calpain caused a down-regulation of cAMP-dependent
protein kinase in AD brain [1109]. Neuronal overexpression of the endogenous inhibitor of calpains,
calpastatin, in a mouse model of AD reduced A␤
pathology [1110].
A-705253 (Abbott, formerly Knoll; Fig. 17) is
an orally active calpain inhibitor for the potential
treatment of AD. A-705253 significantly reduced
cholinergic neurodegeneration caused by A␤ in a
dose-dependent manner in rats [1111–1117]. It also
prevented stress-induced tau hyperphosphorylation in
vitro and in vivo [1118, 1119] (Thomson Reuters
Pharma, update of May 16, 2011).
ABT-957 (Abbott) is a calpain inhibitor for the
potential treatment of neurological disorders including AD (Thomson Reuters Pharma, update of March
2, 2012). The structure was not communicated.
AK-295 (CX-295, Vasolex; AxoTect under license
from Cortex Pharmaceuticals using technology
licensed from Alkermes, Fig. 17) attenuated motor and
cognitive deficits following experimental brain injury
in the rat [1120] (Thomson Reuters Pharma, update of
February 9, 2012).
SNJ-1945 (Senju Pharmaceutical; Fig. 17) is a
potent calpain inhibitor for the potential oral treatment of age-related macular degeneration, retinopathy,
and optic neuritis. Preclinical data were reported
[1121–1124]. Medicinal chemistry papers were contributed [1125–1128] (Thomson Reuters Pharma,
update of April 18, 2012).
The development of calpain inhibitors BDA410 (Mitsubishi-Tokyo Pharmaceuticals), CEP-3122
(Cephalon, now Teva), EP-475 (University of Tennessee), MDL-28170 (Hoechst Marion Roussel, now
sanofi [1129–1131]), and of TH-3501 (University of
Virginia) was terminated.
2.8. Drugs interacting with carbonic anhydrase
Carbonic anhydrase dysfunction impaired cognition
and was associated with mental retardation, AD, and
aging [1132].
The Blanchette Rockefeller Neurosciences Institute is investigating phenylalanine compounds acting
as carbonic anhydrase activators for the potential
treatment of attention deficit disorders and memory
problems in AD (Thomson Reuters Pharma, update of
February 16, 2012).
2.9. Drugs interacting with caspases
Caspases, or cysteine-aspartic proteases or cysteinedependent aspartate-directed proteases, are a family of
cysteine proteases that play essential roles in apoptosis
(programmed cell death), necrosis, and inflammation.
For a review on caspase-6 and neurodegeneration,
see [1133]; for the role of caspases in AD, see
[1134–1138].
NWL-117 (New World Laboratories) is an irreversible inhibitor of active caspase-6 for the
potential treatment of AD (Thomson Reuters Pharma,
update of July 18, 2012). The structure was not
communicated.
2.10. Drugs interacting with
Catechol-O-methyltransferase (COMT)
The topic COMT, cognition, and psychosis was
reviewed [1139–1141]. The potential role of COMT
inhibitors for the treatment of cognitive deficits associated with schizophrenia was described [1142, 1143].
Tolcapone (Tasmar; Roche, launched in 1997)
improved cognition and cortical information processing in normal human subjects [1144]. Tolcapone and
Entacapone (Comtan; Orion in collaboration with
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Novartis launched in 1999) blocked fibril formation of
␣-synuclein and A␤ and protected against A␤-induced
toxicity [1145].
The company Cerecor is investigating COMT
inhibitors for the potential treatment of schizophrenia
including cognition (Thomson Reuters Pharma, update
of April 12, 2012). Structures were not communicated.
2.11. Drugs interacting with cathepsin
Reduction of cathepsin B in transgenic mice
expressing human wild-type A␤PP resulted in significantly decreased brain A␤ [1146, 1147]. Higher
cathepsin B levels were found in plasma of AD patients
compared to healthy controls [1148].
Aloxistatin (E-64d; AB-007; ALP-496; ALSP;
Fig. 17) is an inhibitor of cathepsin B for the potential treatment of AD and traumatic brain injury
[1149–1152]. Aloxistatin was previously evaluated for
the treatment of Duchenne muscular dystrophy by
Taisho Pharmaceuticals, but the development was terminated (Thomson Reuters Pharma, update of June 29,
2012).
Acetyl-L-leucyl-L-valyl-L-lysinal (ALSP) is a cysteine protease inhibitor, which caused a significant
reduction in brain A␤ and ␤-secretase activity by
approximately 50% after i.c.v. administration of
0.06 mg/g brain weight/day for 28 days [1153] (Thomson Reuters Pharma, update of June 28, 2012).
The development of CEL-5A (University of California at Irvine; a cathepsin D inhibitor) and cystatin
C (New York University/Nathan Kline Institute, a cysteine protease inhibitor) was terminated.
2.12. Drugs interacting with cholesterol
24S-hydroxylase (CYP46A1)
Abnormal induction of the cholesterol-catabolic
enzyme CYP46 in glial cells of AD patients was
already recognized in 2001 by researchers at the
Karolinska Institute [1154], followed by [1155–1157].
It was shown that polymorphism in the cholesterol
24S-hydroxylase gene (CYP46A1) associated with
the ApoE␧3 allele increased the risk of AD and
of mild cognitive impairment [1158, 1159]. Similar results were obtained in elderly Chinese subjects
[1160, 1161]. CYP46A1 functional promotor haplotypes decipher genetic susceptibility to AD [1162].
Reviews were published [1163, 1164]. The crystal
structure of the enzyme was elucidated [1165]. The
cDNA cloning was described by scientists from the
577
University of Texas [1166], who generated also KO
mice [1167].
AAV-CYP46A1 (INSERM in collaboration with
sanofi) is an adeno-associated virus gene therapy encoding cholesterol 24-hydroxylase (CYP46A1
gene) for the potential injectable treatment of AD.
Reduced A␤ peptides, amyloid deposits, and trimeric
oligomers were observed in A␤PP23 mice. Significant improvements in cognitive function assessed by
the Morris water maze were also seen in Tau22 mice
[1168] (Thomson Reuters Pharma, update of June 6,
2012). See also Part 3, Chapter 4 Drugs interacting
with Gene Expression.
2.13. Drugs interacting with cyclooxygenase
(COX)
COX (EC 1.14.99.1) is an enzyme that is responsible for the formation of prostaglandins, prostacyclin,
and thromboxane. NSAIDs exert their effects through
inhibition of COX. Oligomers of A␤1-42 induced the
activation of COX-2 in astrocytes [1169].
Epidemiological studies have documented a reduced
prevalence of AD among users of NSAIDs [1170,
1171, 1026, 1172–1178]).
In the Rotterdam study, 6,989 subjects 55 years
of age or older were analyzed for the association of NSAIDs use and AD. The relative risk
of AD was 0.95 in subjects with short-term use
(1 month) of NSAIDs, 0.62 in subjects with
intermediate-term use (1 to 24 months), and 0.20
in those with long-term use (more than 24 months)
[1179]. Several clinical trials using indomethacin,
diclofenac/misoprostol, naproxen, nimesulide, celecoxib, and rofecoxib showed no benefit for AD
patients, reviewed by [1177]. The ADAPT research
group could not show a prevention of AD dementia
in a clinical trial using naproxen and celecoxib [1180,
1181].
The NSAIDs ibuprofen, indomethacin, and sulindac
sulfide preferentially decreased the highly amyloidogenic A␤42 peptide [1172]. This effect was not
mediated by inhibition of COX, but by an allosteric
modulation of ␥-secretase [1064] and by a change in
presenilin 1 conformation [1182]. A list of compounds
decreasing the formation of A␤42 peptide comprising
diclofenac, (R)-flurbiprofen, fenoprofen, ibuprofen,
indomethacin, meclofenamic acid. and sulindac was
presented [1183]. NSAIDs dose-dependently destabilized preformed A␤ fibrils in vitro [1184, 1185]. These
effects were also shown in transgenic mice in vivo
[1025, 1177].
578
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
A␤42 -lowering NSAIDs constitute the founding
members of the new class of ␥-secretase modulators
[1186], vide supra section 2.4.2.
2.14. Drugs interacting with D-amino acid
oxidase
The therapeutic potential of D-amino acid oxidase
(DAAO) inhibitors was described [1187]. Several susceptibility genes for psychiatric disorders have been
identified, among others G72, which is the D-amino
acid oxidase activator [1188–1191].
AS-2651816-00 (Astellas Pharma) is a novel DAAO
inhibitor for the potential treatment of schizophrenia
with an IC50 of 1.5 nM against human DAAO (Thomson Reuters Pharma, update of August 24, 2012). It
is a 3-hydroxy-pyridazin-4(1H)-one, but the precise
structure was not communicated.
Eisai following the acquisition of MGI Pharma
was investigating DAAO inhibitors to enhance the
activity of D-serine. The compound 6-chlorobenzo[d]
isoxazol-3-ol (CBIO) showed an IC50 of 200 nM. Its
development was terminated. Also the development of
DAAO inhibitors of Merck and Pfizer and of SEP227900 (Sunovion) was terminated.
ized in healthy volunteers (n = 100). First results
showed that oral administration of PQ-912 was safe
and well tolerated with relevant therapeutic levels in
blood and CSF (Thomson Reuters Pharma, update of
January 4, 2012). The structure of PQ-912 was not
communicated.
2.16. Drugs interacting with
glyceraldehyde-3-phosphate dehydrogenase
A proteomics analysis of the AD hippocampal
proteome showed an increase of the levels of glyceraldehyde 3-phosphate dehydrogenase [1205]. A
decrease of the activity of cerebral glyceraldehyde-3phosphate dehydrogenase in different animal models
of AD was observed [1206].
Omigapil (SNT-317, TCH-346, CGP-3466; Santhera under license from Novartis; Fig. 18) is an orally
bioavailable glyceraldehyde 3-phosphate dehydrogenase modulator with anti-apoptotic properties for the
treatment of Parkinson’s disease and amyotrophic lateral sclerosis in Phase I clinical trials [1207–1221]
(Thomson Reuters Pharma, update of April 11,
2012).
2.15. Drugs interacting with Glutaminyl Cyclase
2.17. Drugs interacting with glycogen synthase
kinase-3β (GSK-3β)
Glutaminyl cyclase (QC) is an enzyme that catalyzes
the formation of pyroglutamic peptides or proteins
from a N-terminal glutamine residue. Human QC can
perform in parallel the conversion of a N-terminal glutamate of a peptide to a pyroglutamated peptide. When
A␤ is cleaved between amino acids 2 and 3, a peptide with a N-terminal glutamate is formed, which is
cyclized by QC to the N-terminal pyroglutamate. This
transformation renders the molecule more hydrophobic and increases its aggregation velocity [1192–1197].
Hence a QC inhibitor could prevent the formation
of this species [1198–1204]. Secondary glutaminylcyclase inhibitor interactions were presented [4].
PBD-150 (Probiodrug; Fig. 18) is a potent inhibitor
of human glutaminyl cyclase (IC50 = 17 nM) and
totally inhibits formation of A␤3,11 -(pE)40,42 in cell
culture at 1 ␮M (Thomson Reuters Pharma, update of
February 24, 2012).
A second generation of compounds was evaluated,
in which the 1-propyl imidazole residue was replaced
by the more rigid benzimidazole.
PQ-912 (Probiodrug) is a potent QC inhibitor in
Phase I clinical studies with single- and multiple
ascending dose, blinded, placebo-controlled, random-
GSK-3␤ (EC 2.7.11.26, 47 kDa) is a serine/threonine protein kinase ubiquitously expressed
and involved in many cellular signaling pathways
playing a key role in the pathogenesis of AD. It
is probably the link between A␤ and tau pathologies. A␤ activates GSK-3␤ through impairment of
phosphatidyl-inositol-3/Akt signaling. A␤-activated
GSK-3␤ induced hyperphosphorylation of tau, neurofibrillary tangle formation, neuronal death, and
synaptic loss (all found in AD brains). GSK-3␤
induced memory deficits in vivo. Crucial is the
phosphorylation at serine 9. The cited papers are
listed in chronological order: 1999: [1222]; 2002:
[1223–1225]; 2004: [1226–1228]; 2005: [1229]; 2006:
[1230–1232]; 2007: [1233, 1234]; 2008: [1235–1240];
2009: [1241–1243]; 2010: [1244, 1245]; 2011:
[1246–1252]; 2012: [1253–1260].
GSK-3␤ was crystallized and the crystal structure
was resolved [1261, 1262]. 3D-QSAR studies were
reported [1263, 1264]. Ligand-based virtual screening
was elucidated [1265]. Scoring functions were applied
[1266].
Tideglusib (NP-12, NP-031112; Nypta; Noscira,
previously known as Neuropharma; Fig. 18) is the
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
579
Fig. 18. A glyceraldehyde 3-phosphate dehydrogenase modulator, a glutaminyl cyclase inhibitor, 10 glycogen synthase-3␤ and one HDAC
inhibitor.
580
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
lead compound of a series of orally active thiadiazolidinediones, potent inhibitors of GSK-3 [1267]. A
Phase IIb clinical trial in AD patients was initiated in
Spain, Germany, Finland, and the UK in April 2011.
In January 2012, randomization of patients (n = 308)
was completed in the double-blind trial. Preliminary
results are expected by the end of 2012. In December 2009, a Phase II trial for progressive supranuclear
palsy was initiated in the US and in Europe. Enrollment
was completed in October 2010 (n = 125). The drug
was granted orphan status for progressive supranuclear
palsy in November 2009. First positive results of a
clinical pilot study were reported [1268]. (Thomson
Reuters Pharma, update of July 23, 2012).
There are currently many GSK-3␤ inhibitors in preclinical evaluation (in alphabetical order):
AX-9839 (ActivX Biosciences, Kyorin Pharmaceuticals, Fig. 18) is an inhibitor of GSK-3␤ for the
potential treatment of diabetes, AD, and various CNS
disorders [1269] (Thomson Reuters Pharma, update of
April 18, 2012).
CG-9, CG-701338, CG-701446, and CG-701448
(Crystal Genomics) are lead compounds from a series
of GSK-3 inhibitors for the potential treatment of cancer, AD, and schizophrenia (Thomson Reuters Pharma,
update of May 02, 2012). The structures were not communicated.
CP-70949 (Pfizer; Fig. 18) is a selective inhibitor
of GSK-3␤ in preclinical evaluation [1270] (Thomson
Reuters Pharma, update of July 11, 2011).
Dual GSK-3␤/casein kinase 2 modulators (University of Illinois at Chicago) are investigated for the
potential treatment of Alzheimer’s disease. (Thomson
Reuters Pharma, update of September 20, 2012). Structures were not communicated.
GSK-3␤ inhibitors (Pfizer, Fig. 18) investigated a
series of oxazole derivatives. The shown compound
had an IC50 of 5 nM and a more than 100-fold selectivity against all other kinases and met safety criteria
(Thomson Reuters Pharma, update of Aug. 28, 2012).
JI-7263 (Jeil Pharmaceuticals) is the lead compound
from a series of GSK-3␤ inhibitors for the potential treatment of AD and amyotrophic lateral sclerosis
(Thomson Reuters Pharma, update of May 7, 2012).
The structure was not communicated.
Mitsubishi-Tanabe (Fig. 18) presented a potent
GSK-3␤ inhibitor at the AIMECS 11 meeting in Tokyo
with an IC50 of 12 nM (Thomson Reuters Pharma,
update of January 24, 2012).
NNI-362 (NNI-AD; NeuroNascent) is a multikinase
and GSK-3␤ modulator inhibiting several tau phosphorylation sites. Other orally active compounds that
stimulate neuron formation are NNI-X01, NNI-C, and
NNI-251 (Thomson Reuters Pharma, update of July
19, 2012). The structures were not communicated.
NP-101020 (Noscira) is a GSK-3␤ inhibitor for the
potential treatment of AD (Thomson Reuters Pharma,
update of January 12, 2012). The structure was not
communicated.
SN-2127 (AstraZeneca, Fig. 18) is one of several
GSK-3␤ inhibitors in evaluation by AstraZeneca as
are SN-2568, SN-3728, and others (Thomson Reuters
Pharma, update of April 4, 2012).
Takeda (Fig. 18) presented a very potent GSK-3␤
inhibitor with IC50 of 2 nM. After oral administration a significant reduction of tau phosphorylation was
observed in aged JNPL3 mice [1271–1273]; Thomson Reuters Pharma, update of January 04, 2012). The
compound MMBO (Fig. 18) decreased tau phosphorylation and ameliorated cognitive deficits in a transgenic
model of AD [1274]).
TWS-119 (Scripps Research Institute; Fig. 18) is
a compound that can induce neurogenesis in murine
embryonic stem cells. The target of TWS-119 was
shown to be GSK-3␤ by affinity-based and biochemical methods [1275].
VP1.15 (CSIC Madrid and University of Toronto,
Fig. 18) is a dual GSK-3 and PDE7 inhibitor acting as
an antipsychotic and cognitive enhancer in C57BL/6J
mice [1276, 1277].
Extensive programs to identify GSK-3␤ inhibitors
have been ongoing at AstraZeneca [1226, 1278–1280],
at ChemDiv [1281], at GSK (e.g., SB-415286 and
others [1282–1287]), at GVK Biosciences [1288], at
Johnson & Johnson [1289–1292], at Kemia [1293], at
Lilly [1294–1296], at Roche [1297], at Vertex [1298]),
and at Yuyu in collaboration with CrystalGenomics
[1299].
Potent GSK-3␤ inhibitors were described by
researchers at universities (in alphabetical order of
their location): University of Athens [1300], University
Autonoma de Barcelona [1301], Technical University
of Braunschweig [1302], University of Caen [1303,
1304], University of Illinois at Chicago [1305–1310],
Technical University of Darmstadt [1311, 1312, 1312],
Martin-Luther University Halle [1313], University of
La Rochelle [1314], University of Leuven [1231,
1239–1241], CSIC Madrid [1315–1318], University
of Louisiana at Monroe [1319], CNRS/Institut Curie
Orsay [1320], Peking University [1321], Indian Institute of Technology Roorkee [1322], Korea Institute of
Science and Technology Seoul [1323], Fudan University Shanghai [1324], and the University of Talca, Chile
[1325].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
SAR studies on GSK-3␣ inhibitors were published
by researchers at the Technical University Darmstadt,
University of Naples, University of Leuven, and Tel
Aviv University [1326].
The Broad Institute is investigating ATP noncompetitive and allosteric inhibitors of GSK-3␤ (Thomson
Reuters Pharma update of June 3, 2011).
DM-204 (DiaMedica following its acquisition of
Sanomune) is a monoclonal antibody that inhibits
GSK-3␤ (Thomson Reuters Pharma update of June 15,
2012).
The development of AR-A014418 (AstraZeneca)
was terminated [1226, 1278–1280] as was NP-103
(Noscira) and UDA-680 (SAR-502250; Mitsubishi
Pharma and sanofi). Also the development of
Propentofylline (HWA 285; Hoechst Werke Albert,
now sanofi) for AD and for vascular dementia has been
terminated after results of the 72 week propentofylline
long-term use (PLUS) clinical trial showed no treatment differences between the propentofylline-treated
group and the placebo-treated group [1327–1331].
Propentofylline attenuated tau hyperphosphorylation
by reducing the activated form of GSK-3␤ and by
increasing the inactivated form of GSK-3␤ [1332].
Propentofylline is also a potent inhibitor of PDEs
(see section 2.29.). The development of SAN-161
(Sanomune, a subsidiary of DiaMedica), SB-216763
(SmithKline Beecham, now GSK [1333], and the XD4000 series (Xcellsyz, Lonza group) was terminated.
2.18. Drugs interacting with guanylyl cyclase
Soluble guanyl cyclase may be required for
emotional learning and for both reference and
working memory [1334]. A selective irreversible
inhibitor of soluble guanyl cyclase, i.e., 1H-[1,2,4]oxadiazole[4,3-a]-quinoxaline-1-one at doses of 5, 10,
and 20 mg/kg impaired retention for the passive avoidance task in rats. Activation of soluble guanyl cyclase
and cGMP formation in the brain represents one element of effective neuroprotective pathways mediated
by NO [1335]. The design and synthesis of nomethiazoles as NO-chimeras for neurodegenerative therapy
was described [1336].
sGC-1016 (sGC Pharma) is a sustained-release NO
mimetic for the potential treatment of AD in Phase I
clinical trial, which was completed in July 2012 showing high bioavailability (Thomson Reuters Pharma,
update of July 17, 2012). The structure was not communicated.
GT-715 and GT-1061 (Cita NeuroPharmaceuticals,
Vernalis) were prototypes of engineered NO mimetics,
581
which activated soluble guanylyl cyclase and increased
cGMP formation. They improved task acquisition in
cognitively impaired animals and in the 6-OHDA
model of Parkinson’s disease [1337–1341]. The development of both compounds was terminated.
2.19. Drugs interacting with heme oxygenase
Glial heme oxygenase-1 expression in AD and mild
cognitive impairment was reviewed [1342–1346].
OB-28 (Osta Biotechnologies) is a heme
oxygenase-1 inhibitor for the potential injectable
treatment of AD showing statistically significant
improvement in behavioral deficits in double transgenic (A␤PPSWE/PS1dE9) mice (n = 103) after
treatment with 15 or 30 mg/kg/day for 4 months
(Thomson Reuters Pharma update of August 6, 2012).
The structure of OB-28 was not communicated.
2.20. Drugs interacting with histone deacetylase
(HDAC)
An in depth overview shows how to target “the correct” HDAC(s) to treat cognitive disorders [1347]. The
roles of HDAC inhibition in neurodegenerative conditions were discussed [1348]. The role of HDAC6 in
Alzheimer’s disease was discussed [1349]. The loss of
HDAC5 impaired memory function [1350].
EVP-0334 (EnVivo under license from MethylGene) is developing the orally active HDAC inhibitor
as a cognition enhancer for the potential treatment
of AD. A Phase I clinical trial was started in May
2009 and finished in May 2010. Phase II trial are
underway since November 2011. Medicinal chemistry
papers were published [1351, 1352] (Thomson Reuters
Pharma, update of August 10, 2012).
4-Phenylbutyrate (Digna Biotech SL) ameliorated
cognitive deficits and reduced tau pathology in an
AD mouse model [1353–1355], reduced A␤ plaques,
and rescued cognitive behavior in AD transgenic mice
[1356, 1357]. The drug is in Phase I clinical trials for
the potential treatment of AD since April 2010 (Thomson Reuters Pharma update of May 30, 2012).
Other HDAC inhibitors are currently in preclinical
evaluation (in alphabetical order):
CHDI-390576 and CHDI-00381817 (HDAC4
inhibitors) are investigated by the CHDI Foundation in
collaboration with BioFocus DPI (Thomson Reuters
Pharma update of August 10, 2012). The structures
were not disclosed.
Crebinostat (Harvard Medical School, Fig. 18)
is a novel HDAC inhibitor and enhancer of CREB-
582
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
regulated transcription and modulator of chromatinmediated neuroplasticity [1358].
KAR-3010, KAR-3084, and KAR-3166 (Karus
Therapeutics) are HDAC6 inhibitors for the potential oral treatment of immune and inflammatory
disease including AD (Thomson Reuters Pharma
update of July 05, 2012). The structures were not
disclosed.
LB-201 and LB-205 (Lixte Biotechnology) are
drugs that target HDAC and prevent the degradation
and restore the activity of glucocerebrosidase for the
potential treatment of neurological disorders such as
Gaucher’s disease [1359] (Thomson Reuters Pharma
update of April 05, 2012). The structures were not
disclosed.
Dual PKC activators and HDAC inhibitors were
described [1360].
The development of EHT-0205 (ExonHit) was
terminated.
2.21. Drugs interacting with HMG-CoA reductase
The enzyme 3-hydroxy-3-methyl-glutaryl-CoA
reductase (EC 1.1.1.88) is the rate-controlling enzyme
of the mevalonate pathway, which produces cholesterol and other isoprenoids. It is the target of the
statins (or HMG-CoA reductase inhibitors). In a
large study comprising 9,844 participants at ages
from 40 to 45 years the risk of AD was evaluated in
relation to cholesterol levels. The analyses revealed
that cholesterol levels >220 mg/dL were a significant
risk factor for AD [1361]. See also the review [1362].
A lower prevalence of probable AD in a cohort of
patients taking lovastatin or pravastatin between 60
and 73% (p < 0.001) lower than the total patient population or compared with patients taking other medications typically used for the treatment of hypertension or
cardiovascular disease was found [1363–1367]. Excellent reviews were provided [1368–1375]. The link
between altered cholesterol metabolism and AD was
described [1376]. Statins, risk of dementia, and cognitive function were discussed [1377].
Statins can shift A␤PP processing to the nonamyloidogenic ␣-secretase pathway, e.g., simvastatin,
which in addition prevented neuroinflammation and
oxidative stress [1378, 1379], atorvastatin, which in
addition prevented neuroinflammation [1380, 1381]
and lovastatin, which in addition stimulated the upregulation of ␣7 nicotinic acetylcholine receptors [1382,
1383]. A␤40 blocked cerebral perivascular sympathetic ␣7-nAChRs, which was prevented by statins
such as mevastatin and lovastatin [1384, 1385].
Pitavastatin attenuated celecoxib- and streptozotocininduced experimental dementia [1386]. Atovastatin
and pitavastatin reduced senile plaque and phosphorylated tau in aged A␤PP mice [1387, 1388].
These promising biological results in experimental
animals were not confirmed in extensive clinical trials.
Only a slight reduction of cognitive decline in a large
study including 3,334 participants was found [1389].
A post hoc analysis from three double-blind, placebocontrolled, clinical trials of galantamine in patients
with AD was done [1390]. Patients were divided into
four treatment groups, statin plus galantamine (n = 42),
statin alone (n = 50), galantamine alone (n = 614),
and placebo (n = 619). Galantamine was associated
with a significant beneficial effect on cognitive status (p < 0.001). The use of statins did not produce a
significant beneficial effect (p = 0.083).
A proof-of-concept randomized controlled trial of
Atorvastatin (Lipitor, Pfizer, launched in 1996) indicated a trend for symptomatic benefit in mild to
moderate AD patients [1391–1393]. But the large
LEAD (Lipitor’s effect in Alzheimer’s Dementia)
study in 640 patients, who were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by
a double-blind, 8-week atorvastatin withdrawal phase
did not show a significant benefit for cognition as
measured by ADAS-cog (p = 0.26) or for global function as measured by ADCS-Clinical Global Impression
of Change (p = 0.73) compared with placebo [1394,
1395]).
Pravastatin (Pravachol, Mevalotin; Daiichi
Sankyo, launched in 1989) was evaluated in PROSPER (Prospective Study of Pravastatin in the Elderly
at Risk) in 5,804 participants at six different time
points. No difference in cognitive decline was found
in patients treated with pravastatin compared to
placebo (p > 0.05). During a three year follow-up
period no effect on cognitive decline was observed
[1396].
Simvastatin (Zocor, MK-0733; Merck launched
in 1989) was evaluated in a 406 patient Phase III
study conducted by the National Institute of Aging.
Patients were treated with 20 mg simvastatin per day
for six weeks and with 40 mg/day simvastatin for
an additional 18 months. Simvastatin lowered lipid
levels, but had no effect on change of ADAS-cog
score or on secondary outcome measures [1397–1403].
Chronic simvastatin treatment rescued cognitive function in a transgenic mouse model of AD and enhanced
LTP in the CA1 region of the hippocampus in slices
from C57BL/56 mice via inhibition of farnesylation
[1404–1406].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
583
Fig. 19. One HMG-CoA-reductase, 7 kinase and one kynurenine aminotransferase II inhibitor(s).
NST-0037 (Neuron BioPharma; Fig. 19) is a natural small molecule HMG-CoA-reductase inhibitor,
which also has neuroprotective, antioxidant, and
anti-convulsive activity. The synthesis was described
[1407]. Potential follow-up compounds are NST-0005
and NST-0060, whereas the development of NST-0021
was terminated (Thomson Reuters Pharma, update of
June 13, 2012).
584
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
2.22. Drugs interacting with insulin-degrading
enzyme
The role of insulin-degrading enzyme in AD was
discussed [1408, 1409]. The expression and functional
profiling of insulin-degrading enzyme in elderly and
AD patients was reported [1410] as was the characterization in human serum [1411].
The company Inventram is investigating insulindegrading enzyme activators for the potential treatment
of type 2 diabetes and AD (Thomson Reuters Pharma,
update of April 20, 2012). No structures were communicated.
2.23. Drugs interacting with Kinases ( =
/ GSK-3β
and =
/ PKC)
Advances in the development of kinase inhibitor
therapeutics for AD were presented [1412]. Noteworthy is that acetyl-L-carnitine (ST-200, Nicetile,
Zibren; launched by Sigma-Tau in Italy in 1985 and
in South Korea in 1995 as a memory enhancer) ameliorated spatial memory deficits induced by inhibition
of phosphoinositol-3-kinase and PKC [1413]. Also
clioquinol seems to operate in a similar way [1414].
Masitinib (AB-1010, AB Science; Fig. 19) is an
inhibitor of c-kit, Lyn and PDGF-R kinases. It was
evaluated in a Phase II clinical trial as an adjunct
therapy to cholinesterase inhibitor and/or memantine
in 26 patients with mild-to-moderate AD versus
placebo (n = 8). The masitinib treated patients showed
improvements in MMSE scores, the ADAS-Cog and
the Alzheimer’s Disease Cooperative Study Activities
of Daily Living Inventory with statistical significance
between treatment arms at week 12 and/or week
24 (p = 0.016 and 0.030, respectively) [1415]. In
September 2010, EMA approved a pivotal Phase III
trial in 300 AD patients to assess safety and efficacy of
6 mg/kg/day masitinib over 24 weeks. The biological
characterization was described [1416] (Thomson
Reuters Pharma, update of August 10, 2012). Numerous other kinase inhibitor therapeutics are currently
in preclinical evaluation (in alphabetical order):
AIK-2, AIK-2a, AIK-2c, and AIK-21 (Allinky
Biopharma) are non-ATP-competitive MAP kinase
inhibitors for the potential treatment of cerebrovascular stroke and AD (Thomson Reuters Pharma, update
of October 28, 2011). The structures were not communicated.
Beta carboline alkaloids (Translational Genomics
Research Institute) including harmol (Fig. 19) inhibit
dual specificity tyrosine phosphorylation regulated
kinase 1A (DYRK1A) and tau phosphorylation
(IC50 = 90 nM). (Thomson Reuters Pharma, update of
June 8, 2012).
Cadeprin (group S8A serine protease) antagonists
are investigated by researchers from the Universities
of Strathclyde and Glasgow [1417] (Thomson Reuters
Pharma, update of May 3, 2012).
Casein kinase 1δ inhibitors (Proteome Sciences),
such as PS-110 and PS-278, are investigated for the
potential treatment of AD. (Thomson Reuters Pharma,
update of July 2, 2012). Structures were not communicated.
CDK5/p25 inhibitors (Pfizer) are investigated for
the potential treatment of AD. A novel pyrrolo[3,2b]pyridine derivative (Fig. 19) displayed low nM
potency. (Thomson Reuters Pharma, update of April
14, 2011).
CZC-25146 (GSK, following its acquisition of
Cellzome) is leucine-rich repeat kinase 2 (LRRK2)
inhibitor for the potential treatment of Parkinson’s disease. [1418] (Thomson Reuters Pharma, update of June
1, 2012).
Dasatinib (Bristol-Myers Squibb, launched 2006), a
Src tyrosine kinase inhibitor, attenuated A␤ associated
microgliosis in a murine model of AD [1419].
DYRK-1 alpha protein kinase inhibitors (Arrien
Pharmaceuticals) are evaluated for the potential
treatment of Alzheimer’s disease and Down syndrome.
(Thomson Reuters Pharma, update of April 24, 2012).
Structures were not communicated.
DYRK-1 alpha protein kinase inhibitors (Carna
Biosciences) is a program in the stage of lead optimization. (Thomson Reuters Pharma, update of March 16,
2012). Structures were not communicated.
FRAX-120, FRAX-355, and FRAX-486 (Afraxis)
showed IC50 values of 23, 58, and 14 nM for p21activated kinase. The drugs have a potential for the
treatment of fragile X syndrome, autism, schizophrenia, and AD (Thomson Reuters Pharma, update of
August 14, 2012). Structures were not communicated.
G-2019S (Zenobia Pharmaceuticals in collaboration with Johns Hopkins University) is a LRRK2
inhibitor for the potential treatment of Parkinson’s disease (Thomson Reuters Pharma, update of March 13,
2012). The structure was not communicated.
Hydroxy-fasudil (Fig. 19, Asahi Kasei Pharma
Corp.), a rho kinase (ROCK) inhibitor, improved
spatial learning and working memory in rats in
a water radial-arm maze [1420]. ROCK inhibition
led to an increase of Rac1 activity and to an
activation of PKCζ which in turn phosphorylated
KIBRA involved in the formation of memory [1421].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
ROCK inhibition prevented tau hyperphosphorylation
[1422].
KIBRA pathway modulators (Amnestix Inc., a
wholly owned subsidiary of SYGNIS Pharma) offer a
new genetic link to cognition that may benefit patients
suffering from AD. For the association of KIBRA and
late onset AD, see [1423], for enhancement of cognition in anxiety disorders [1424] (Thomson Reuters
Pharma, update of August 14, 2012).
LDN-22684 (Sirtris Pharmaceuticals) is a LRRK2
inhibitor for the potential treatment of Parkinson’s disease [1425] (Thomson Reuters Pharma, update of June
17, 2011). The structure was not communicated.
LRRK2 inhibitors (Arrien Pharmaceuticals) are
investigated for the potential oral treatment of
Parkinson’s disease (Thomson Reuters Pharma,
update of May 18, 2012). The structures were not
communicated.
LRRK2 inhibitors (Genentech, Fig. 19) are investigated for the potential treatment of Parkinson’s
disease. The medicinal chemistry was described
[1426]. (Thomson Reuters Pharma, update of June 26,
2012). The lead structure was communicated.
LRRK2 inhibitors (Genosco, Oscotec Inc.) are
investigated for the potential treatment of Parkinson’s
disease (Thomson Reuters Pharma, update of April 20,
2012). The structures were not communicated.
LRRK2 inhibitors (Oncodesign Biotechnology)
are investigated for the potential treatment of cancer
and CNS diseases including Parkinson’s disease
(Thomson Reuters Pharma, update of April 2, 2012).
The structures were not communicated.
LRRK2 inhibitors (Origenis GmbH) are investigated for the potential treatment of Parkinson’s disease
(Thomson Reuters Pharma, update of May 11, 2012).
The structures were not communicated.
LRRK2 inhibitors (Pfizer) are investigated for the
potential treatment of Parkinson’s disease (Thomson
Reuters Pharma, update of June 20, 2012). The structures were not communicated.
LRRK2 inhibitors (Vernalis/Lundbeck) are investigated for the potential treatment of Parkinson’s
disease (Thomson Reuters Pharma, update of May 02,
2012). The structures were not communicated.
MARK inhibitors (microtubule affinity regulating kinase; Medical Research Council Technology,
MRCT) are investigated for the inhibition of tau phosphorylation (Thomson Reuters Pharma, update of June
1, 2012).
MARK3 inhibitors (microtubule affinity regulating kinase 3, CDC25-associated kinase-1; Merck) are
in preclinical evaluation for the potential treatment of
585
AD. The pyrazolo[1,5-a]pyridine compound (Fig. 19)
showed t1/2 ’s in rat, dog, and Rhesus monkey of 3.5,
2.3, and 1.4 hours, respectively (Thomson Reuters
Pharma, update of April 14, 2011).
Minokine (MW01-2-069A-SRM; Northwestern
University; Fig. 19) is a p38 MAP kinase inhibitor for
the potential oral treatment of neurodegenerative diseases including AD (Thomson Reuters Pharma, update
of April 27, 2011).
NNI-351 (NNI-depression, NNI-DS, NeuroNascent; Fig. 19) is an orally active compound
preventing stress-induced neurogenesis reduction
via inhibition of dual specificity tyrosinephosphorylation-regulated kinase 1 alpha (DYRK-1␣)
protein (Thomson Reuters Pharma, update of March
22, 2012).
P-005 (NB Health Laboratory) is a small molecule
highly selective kinase inhibitor for the potential treatment of AD (Thomson Reuters Pharma, update of
December 23, 2011). The structure was not communicated.
Protein kinase inhibitors (ManRos Therapeutics)
are evaluated as AD medication (Thomson Reuters
Pharma, update of February 24, 2011). The structures
were not communicated.
SEL-103 (Selvita Life Sciences Solutions) is a program in collaboration with Orion Corporation, Espoo
Finland, to investigate novel, orally bioavailable and
highly selective small molecules for the potential
treatment of multiple cognitive disorders including
AD (Thomson Reuters Pharma, update of July 4,
2012).
SEL-141 (Selvita Life Sciences Solutions) is a program targeting kinases involved in tau phosphorylation
for the potential treatment of AD, Down syndrome, and
cognitive disorders. Focus is on DYRK1A (Thomson
Reuters Pharma, update of July 4, 2012). Structures
were not communicated.
Sorafenib, a small molecular inhibitor of tyrosine protein kinases (VEGFR and PDGFR) and of
raf restored working memory in A␤PPSWE transgenic
mice [1427].
TTT-3002 (TauTaTis) is a multi-targeted kinase
inhibitor that can inhibit the LRRK2 gene and tumor
growth for the potential treatment of Parkinson’s disease, AD, and cancer. (Thomson Reuters Pharma,
update of January 25, 2012). The structure was not
communicated.
URMC-099-C (Califia, the University of Nebraska
Medical Center and the University of Rochester) is an
inhibitor of mixed lineage kinase-3 for the treatment
of HIV-associated neurocognitive disorder (Thomson
586
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Reuters Pharma, update of June 5, 2012). The structure
was not communicated.
Inhibitors of the protein kinase c-raf1, such as GW5074 and ZM-336372, protected cortical cells against
A␤ toxicity [1428].
The development of AIKb2 (Allinky Biopharma;
a MAP kinase inhibitor), BA-1001 (BioAxone; a
rho kinase inhibitor [1429]), GW-5074 (GSK, a craf1 inhibitor), ORS-1006 (Arrien Pharmaceuticals, a
LRRK2 inhibitor), Pan-MLK inhibitors (Cephalon,
now Teva), PLX-3397 (Plexxikon, a subsidiary of Daiichi Sankyo; an oral small-molecule dual Fms/kit and
Flt3-ITD inhibitor; a Phase II trial for the treatment
of acute myelogenous leukemia continues), RS-4073
(Daiichi Sankyo; a potentiator of TrkA and Map
kinase activation), SB-203580 (SmithKline Beecham,
now GSK; a protein kinase and cytokine suppression
binding protein (CSBP)/p38 inhibitor [1430], SCIO323 (Scios, a p38 kinase inhibitor), SRN-003-556
(SIRENADE Pharmaceuticals; an ERK2 inhibitor),
and of ZK-808762 (University of Göttingen; a
serine protease and Factor Xa inhibitor) was
terminated.
2.24. Drugs interacting with kynurenine
mono-oxygenase and kynurenine
transaminase II
The kynurenine metabolism in AD was described
[1431]. Reduction of kynurenic acid formation
enhanced hippocampal plasticity and cognitive
behavior [1432]. Crystal structure-based selective targeting of kynurenine aminotransferase II for cognitive
enhancement was discussed [1433].
CHDI-003940246 and CHDI-00340246 (Evotec in
collaboration with the CHDI Foundation) are kynurenine mono-oxygenase inhibitors for the potential
treatment of Huntington’s disease (Thomson Reuters
Pharma, update of January 10, 2012). The structures
were not communicated.
PF-04859989 (Pfizer, Fig. 19) is an inhibitor of
kynurenine (oxoglutarate) aminotransferase II for the
potential treatment of schizophrenia [1434] (Thomson
Reuters Pharma, update of March 21, 2012).
2.25. Drugs interacting with 5-lipoxygenase
The enzyme 5-lipoxygenase (5-LO) catalyzes the
conversion of arachidonic acid to 5-hydroxy-peroxyeicosatetraenoic acid (5-HPETE) and subsequently
to 5-hydroxy-eicosatetraenoic acid (5-HETE), which
are metabolized to different leukotrienes [1435]. The
group of Domenico Pratico found that A␤ deposition
in brains of Tg2576 mice lacking 5-LO was reduced
by 64 to 80%, suggesting that pharmacological inhibition of 5-LO could provide a novel therapy for AD
[1436]. Additional investigations showed that 5-LO
regulated the formation of A␤ by activating the cAMPresponse element binding protein (CREB), which in
turn increased transcription of the ␥-secretase complex
[1437, 1438].
In a Letter to the Editor of Annals of Neurology,
Kenji Hashimoto [1439] suggested to test minocycline, which protected PC12 cells against NMDAinduced injury via inhibiting 5-lipoxygenase activation
[1440].
Minocycline (Wyeth, now Pfizer and Takeda
launched in 1999) is a second generation tetracycline that effectively crosses the blood brain barrier.
It improved cognitive impairment in AD models
[1441]. It provided protection against A␤25-35 induced
alterations of the somatostatin signaling pathway
[1442, 1443]. It reduced microglial activation [1444,
1445] and A␤-derived neuroinflammation [1446].
It recovered MTT-formazan exocytosis impaired by
A␤ [1447]. Minocycline inhibited ␤-secretase-1 in
a transgenic model of AD-like amyloid pathology
[1448]. It reduced the development of abnormal tau
species in models of AD [1449–1451]. Minocycline
improved negative symptoms in patients with early
schizophrenia [1452].
A new class of 5-lipoxygenase inhibitors was communicated recently [1453].
2.26. Drugs interacting with monoamine oxidase
Recent efforts of medicinal chemists to explore
ligands targeting MOAs were reviewed [1454]. A
patent-related survey on new MOA inhibitors was published [1455]. The changes of MAO A and B in AD
were elucidated [1456] as was the platelet MAO B
activity in dementia [1457].
Ladostigil (TV-3326; Avraham Pharmaceuticals
under license from Yissum Research Development, a
wholly owned company of the Hebrew University of
Jerusalem; see Fig. 8) is a dual acetylcholine esterase
and MAO inhibitor currently in Phase II clinical trials in 190 patients in Europe since December 2010
(Thomson Reuters Pharma, update of May 18, 2012).
See section 2.1.1.9. Dual AChE and MAO inhibitors.
RG-1577 (RO-4602522; EVT-302; Roche under
license from Evotec) is an orally active, selective,
and reversible MAO-B inhibitor. The company was
planning to start a Phase II trial in patients with AD
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
in the second half of 2012 (Thomson Reuters Pharma,
update of August 8, 2012). Its structure was not
communicated.
OG-45 (Oryzon Genomics) is a dual MAO-B
inhibitor and lysine specific demethylase-1 inhibitor.
(Thomson Reuters Pharma, update of April 16, 2012).
Its structure was not communicated.
VAR-10200 (HLA-20; Varinel; Fig. 20) is a dual
iron-chelating agent and MAO-B inhibitor for the
potential treatment of age-related macular degeneration [1458] (Thomson Reuters Pharma, update of
February 24, 2012).
VAR-10300 (M-30; Varinel, Technion and the
Weizmann Institute of Science; Fig. 20) combines
the iron-chelating properties of 8-hydroxy-quinoline
with the MAO inhibitor moiety of rasaglinine [470,
1459–1465] (Thomson Reuters Pharma, update of May
15, 2012).
Rasagiline (TVP-1012; (R)-enantiomer; Azilect;
marketed by Teva and Lundbeck; Fig. 20) proved to be
a very valuable drug for the treatment of Parkinson’s
disease with sales in 2011 of USD 290 million reported
by Teva and USD 221 million reported by Lundbeck.
Rasagiline was extensively characterized (in chronological order) [1466–1478]. The effects of rasagiline on
cognitive deficits in cognitively-impaired Parkinson’s
disease patients were evaluated [1479]. A␤PP processing properties of rasagiline were described [1480].
Rasagiline improved learning and memory in young
healthy rats [1481]. In July 2004 Eisai initiated Phase
II clinical trials in the US for the treatment of AD, later
also in combination with donepezil. In March 2008
development for the indication AD was discontinued
(Thomson Reuters Pharma, update August 29, 2012).
Safinamide (FCE-26743; NM-1015, PNU151774E; Zambon under license from Newron, who
acquired the rights from Pharmacia and Upjohn,
now Pfizer; Fig. 20) is a potent MAO B inhibitor
(IC50 = 98 nM; MAO A: IC50 = 580 ␮M, selectivity
index: 5,918 for the potential treatment of Parkinson’s
disease and AD [1482]. The first synthesis was
described in 1998 [1483] followed by the solid-phase
synthesis [1482]. The enantiomeric separation of
safinamide was disclosed [1484]. The biological
characterization was described in detail [1485–1487].
Several reviews were published [1488–1490]. Phase
III trials in early Parkinson’s disease patients began
in June 2004. An expert opinion on safinamide in
Parkinson’s disease was published [1491]. A Phase
III trial in AD patients was abandoned in late 2007
(Thomson Reuters Pharma, update of August 21,
2012).
587
The development of many other MAO inhibitors
for the indication AD was terminated, of bifemelane
(MCI-2016; SON-216; Sosei under license from Mitsubishi [1492, 1493]), EVT-301 (Evotec under license
from Roche), EXP-631 (Bristol-Myers Squibb),
4-fluoroselegiline (Chinoin, now sanofi), HT-1067
(Helicon Therapeutics), indantadol (Vernalis under
license from Chiesi), lazabemide (Ro 19-6327; Roche
[1494–1496]), milacemide (GD Searle, now Pfizer
[1497–1499]), NW-1772 (Newron Pharmaceuticals),
PF-9601N (University of Autonoma de Barcelona),
Ro-41-1049 (Roche), SL-25.1188 and SL-34.0026
(both sanofi) and of YY-125 (Yuyu Inc.).
2.27. Drugs modulating O-linked
N-acetylglucosaminidase (O-GlcNAcase;
OGA)
O-GlcNAcase is the enzyme that plays a role in
the removal of N-acetylglucosamine groups from serine and threonine residues in both the nucleus and
the cytoplasm of cells [1500, 1501]. O-GlcNAcase
may compete with phosphorylation of the same serine or threonine residues. Studies to elucidate the
binding mode were carried out by [1502, 1503].
O-GlcNAcylation directly regulates core components
of the pluripotency network [1504].
Alectos Therapeutics/Merck are investigating
O-GlcNAcase modulators (Thomson Reuters Pharma
updates of July 5, 2012).
GlcNAcstatin (University of Dundee in collaboration with Aquapharm Biodiscovery; Fig. 20) is a
marine natural product for the potential treatment of
AD [1505, 1506]. For an efficient and versatile synthesis of GlcNAcstatin derivatives, see [1507] (Thomson
Reuters Pharma, update of January 23, 2012).
NButGT (Seoul National University; Fig. 20),
a specific inhibitor of O-GlcNAcase, reduced A␤
production by lowering ␥-secretase activity both in
vitro and in vivo. O-GlcNAcylation takes place at the
S708 residue of nicastrin, a component of ␥-secretase
[1508] = [5]. The synthesis was described by chemists
of the Simon Fraser University [6].
SEG-4 (Summit Corporation) inhibited OGA with
IC50 and Ki values of 10 and 72 nM, respectively. The
compound significantly reduced tau phosphorylation
(Thomson Reuters Pharma, update of August 2, 2012).
The structure was not communicated.
Thiamet-G (Simon Fraser University) is a
potent inhibitor of human O-GlcNAcase (Ki = 21 nM;
Fig. 20) and efficiently reduced phosphorylation of
tau at Thr231, Ser396, and Ser422 in both rat cor-
588
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 20. Four monoamine oxidase and three O-linked N-acetylglucosaminidase inhibitors.
tex and hippocampus [1509–1512]. For commentaries
see [1513, 1514]. Acute thiamet G treatment led to
a decrease in tau phosphorylation at Thr181, Thr212,
Ser214, Ser262/Ser356, Ser404, and Ser409 and an
increase in tau phosphorylation at Ser199, Ser202,
Ser396, and Ser422 in mouse brain, probably via stimulation of GSK-3␤ activity [1515].
2.28. Drugs interacting with peptidyl-prolyl
cis-trans isomerase D
Peptidyl-prolyl cis-trans isomerase D or Cyclophilin
D (Cyp D; EC 5.2.1.8. Isomerase) is implicated in cell
death pathways. Blockade of Cyp D could be a potent
therapeutic strategy for degenerative disorders such as
AD, ischemia, and multiple sclerosis [1516]. Soluble
A␤ is also found in mitochondria, where it interacts
with Cyp D, a component of the mitochondrial permeability transition pore. Interference with the normal
functions of this protein resulted in disruption of cell
homeostasis and ultimately cell death [1517].
The Hsp90-associated cis-trans peptidyl-prolyl
isomerase-FK506 binding protein 51 (FKBP51) was
recently found to co-localize with the microtubuleassociated protein tau in neurons and physically
interact with tau in brain tissues from humans, who
died from AD [1518].
PIN1 is a peptidyl-prolyl isomerase, which catalyzes
cis-trans isomerization of peptide bonds N-terminal
to specific phospho-serine/threonine-proline motifs.
PIN1 isomerizes phosphorylated tau and thus restores
the ability of phosphorylated tau to bind microtubules,
and eventually promote dephosphorylation of tau by
PP2A phosphatase [1519].
Scynexis is investigating a series of Cyp D inhibitors
for the potential treatment of muscle injury, ischemia,
reperfusion injury, trauma, and neurodegenerative disease (Thomson Reuters Pharma, update of June 28,
2011).
2.29. Drugs interacting with phosphodiesterases
Several excellent reviews on PDE inhibition and
cognition enhancement were published [1520–1524].
Based on the expression of PDE mRNA in the
human brain, it was suggested that PDE1 and PDE10
inhibitors are strong candidates for the development
of cognition enhancers. Chronic PDE type 2 inhibition with BAY60-7550 improved memory in the
A␤PPswe/PS1dE9 mouse model of AD [1525]. The
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
medicinal chemistry of PDE4D allosteric modulators
[1526], of PDE4 inhibitors [1527], of PDE5 inhibitors
[1528, 1529], and of PDE10A inhibitors was reviewed
[1530, 1531].
Etazolate (EHT-202; SQ-20009; Exonhit; see
Fig. 10) is an orally active PDE4 inhibitor and anxiolytic GABAA receptor modulator, which shifts A␤PP
processing toward the ␣-secretase pathway [503, 504,
1532–1536]. The results of the first Phase II 3-month,
randomized, placebo-controlled, double-blind study in
AD patients was reported [505] (Thomson Reuters
Pharma, update of September 13, 2011). See also section 2.2. Drugs interacting with ␣-secretase.
PF-02545920 (MP-10; Pfizer; Fig. 21) is a PDE10A
inhibitor in a randomized, double-blind, placebocontrolled Phase II clinical trial in patients with
acute schizophrenia (n = 260) since October 2010.
PF-02545920 is also evaluated for the treatment of
Huntington’s disease [1531, 1537–1540]. (Thomson
Reuters Pharma, update of July 19, 2012).
Lu-AF11167 (Lundbeck) is an inhibitor of a brainexpressed PDE enzyme for the potential treatment of
AD, Huntington’s chorea, and schizophrenia in a Phase
I clinical trial since March 2011 (Thomson Reuters
Pharma, update of August 8, 2012). The structure was
not communicated.
There are several PDE inhibitors in preclinical evaluation (in alphabetical order):
AMG-7980 (Amgen, Fig. 21) is a novel PDE10A
inhibitor with a Ki of 0.94 nM useful as tritiated
ligand to measure PDE10A target occupancy in rat
brain [1541, 1542].
AVE-8112 (Aventis, now sanofi and Michael J.
Fox Foundation) is a PDE4 inhibitor for the potential treatment of Parkinson’s disease. In April 2012,
a US Phase Ib study was planned (Thomson Reuters
Pharma, update of May 30, 2012). The structure was
not communicated.
BCA-909 (BCR-909; Boehringer Ingelheim under
license from biocrea GmbH) is a PDE2 inhibitor for
the potential treatment of mild cognitive impairment
in schizophrenia and AD (Thomson Reuters Pharma,
update of May 30, 2012). The structure was not
communicated.
Cilostazol (Otsuka), a selective PDE3 inhibitor, protected against A␤1-40 -induced suppression of viability
and neurite elongation [1543].
Dual PDE10/PDE 2 inhibitors (biocrea GmbH)
are investigated for the potential treatment of
schizophrenia and AD (Thomson Reuters Pharma,
update of January 18, 2012). Structures were not
communicated.
589
GEBR-7b (University of Genoa; Fig. 21) is a novel
PDE4D selective inhibitor that improves memory in
rodents at non-emetic doses [1544] (Thomson Reuters
Pharma, update of December 21, 2011).
ITI-002A, IC-200214, and ITI-214 (Takeda
under license of Intra-Cellular Therapies) are PDE1
inhibitors for the potential oral treatment of cognitive disorders associated with schizophrenia (Thomson
Reuters Pharma, update of July 30, 2012). The structures were not communicated.
OMS-182410 (Omeros) is a PDE10 inhibitor for
the potential treatment of schizophrenia (Thomson
Reuters Pharma, update of July 19, 2012). The structure was not communicated.
PDE2A inhibitor (Pfizer, Fig. 21) is evaluated for
the potential treatment of cognitive impairment associated with schizophrenia. In March 2012, a PDE2A
inhibitor with an IC50 of 4 nM was presented at the
243rd ACS Meeting in San Diego (Thomson Reuters
Pharma, update of August 24, 2012).
Allosteric PDE4 inhibitors (Tetra Discovery Partners; West Virginia University) are evaluated for
the potential treatment of mild cognitive impairment
(Thomson Reuters Pharma, update of July 5, 2012).
Structures were not communicated.
PDE7 inhibitors (Omeros) are a potential new
treatment of Parkinson’s disease (Thomson Reuters
Pharma, update of May 23, 2012). The structures were
not communicated.
A PDE9 inhibitor (Pfizer; Fig. 21) for the potential
treatment of AD was found to penetrate mouse brain
and had a half-life of 6.8 hour in dog (Thomson Reuters
Pharma, update of April 14, 2011).
A PDE10 inhibitor (biocrea, a spin-out from BioTie
Therapeutics following its acquisition of elbion,
Fig. 21) is investigated for the potential treatment
of Huntington’s disease. (Thomson Reuters Pharma,
update of May 29, 2012).
1 8F-PF-0430 (Pfizer, Fig. 21) is a PDE2-selective
CNS PET ligand for the potential diagnosis of
Alzheimer’s disease. (Thomson Reuters Pharma,
update of October 03, 2012).
PF-999 (Pfizer, Fig. 21) is a PDE2A inhibitor for the
potential treatment of cognitive impairment associated
with schizophrenia. (Thomson Reuters Pharma, update
of September 6, 2012).
Sildenafil (Pfizer, launched as Viagra in 1998) and
Tadalafil (Lilly launched as Cialis in 2003), potent
PDE5 inhibitors, restored cognitive function without
affecting A␤ burden in a mouse model of AD. Tadalafil
reversed cognitive dysfunction in a mouse model of AD
[1545, 1546].
590
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 21. Ten phosphodiesterase inhibitors and a phospholipase A2 inhibitor.
THPP-1 (Merck, Fig. 21) is a potent, orally bioavailable PDE10A inhibitor, which improved episodic-like
memory in rats and executive function in Rhesus monkeys [1547].
VP1.15 (CSIC Madrid and University of Toronto,
Fig. 18) is a dual GSK-3 and PDE7 inhibitor acting as
an antipsychotic and cognitive enhancer in C57BL/6J
mice [1276, 1277].
The development of many PDE inhibitors was
terminated, of D-159687 and DG-071 (deCODE
genetics, now DGI Resolution), denbufylline (BRL30892; SmithKline Beecham, now GSK [1548]),
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
HT-0712 (IPL-455903; Helicon under license from
Orexo; a PDE4 inhibitor, Fig. 21 [1549, 1550]), IC-041
(Intra-Cellular Therapies), KS-505a (Kyowa Hakko
Kirin), of MEM-1018, MEM-1091, MEM-1414
(R-1533) and MEM-1917 (Memory Pharmaceuticals, now Roche), MK-0952 (Merck, a selective
PDE4 inhibitor [1551]), NVP-ABE171 (Novartis
[1552–1554]), PF-4181366 and PF-04447943 (Pfizer;
a PDE9A inhibitor [1555, 1556]), PQ-10 (Pfizer),
propentofylline (HWA 285; Hoechst Werke Albert,
now sanofi [1327–1329, 1331, 1332, 1557, 1558]),
R-1627 (Roche), rolipram (Meiji Seika under license
from Bayer Schering Pharma [1521, 1559–1566]),
V-11294A (Napp Pharmaceutical Group) and
YF-012403 (Columbia University, a PDE5 inhibitor).
2.30. Drugs interacting with Phospholipase A2
and D2
Phospholipase A2 reduction ameliorated cognitive
deficits in a mouse model of AD [1567–1569]. These
findings were confirmed by genetic phospholipase A2
and D2 ablation studies [1570–1572].
Rilapladib (SB-659032; GSK using a technology licensed from Human Genome Science; Fig. 21)
is a lipoprotein-associated phospholipase A2 (LPPLA2) inhibitor for the potential oral treatment of
atherosclerosis and AD. In October 2011 a randomized, double-blind, placebo-controlled Phase II study
was initiated in 120 AD patients with evidence of
cardiovascular disease in Europe. The study was scheduled to complete in November 2012 (Thomson Reuters
Pharma, update of June 26, 2012).
Icosapent ethyl (AMR-101, SC-111, LAX-101;
MND-21; Epadel; ethyl-eicosapentaenoic acid;
Mochida Pharmaceutical and Amarin under license
from Scotia Holdings), a phospholipase A2 inhibitor,
was launched in Japan for the treatment of arteriosclerosis obliterans. The drug was in Phase IIa
clinical trials for the treatment of AD by Mochida,
which were completed in May 2007 and in Phase IIa
clinical trials for the treatment of memory disorders
in age-associated memory impairment in the UK by
Amarin, which started in May 2008. By 2011 the
development for age-associated memory impairment
was discontinued (Thomson Reuters Pharma, update
of August 29, 2012).
2.31. Drugs interacting with plasminogen
activator inhibitor (PAI)
PAI-1 (serpin E1) is a serine protease inhibitor
that functions as the principal inhibitor of tissue
591
plasminogen activator (tPA) and urokinase, the activators of plasminogen and hence fibrinolysis [1573].
Elevated serum PA1-1 was associated with a high
risk for cognitive dysfunction [1574]. PAI-1 promoted
synaptogenesis and protected against A␤1-42 -induced
neurotoxicity [7]. PAI-1 was also related to lower
speed and visuomotor coordination in elderly subjects
[1575]. PAI-1 may be a useful marker for vascular
dementia [1576]. The plasmin system of AD patients
was discussed [1577].
IMD-4482 (Institute of Medicinal Molecular
Design, IMMD) is an inhibitor of PAI-1 for the potential treatment of fibrotic diseases. The indication AD
is no longer followed up (Thomson Reuters Pharma,
update of January 19, 2012).
The development of the PAI aleplasinin (PAZ-417;
Wyeth, now Pfizer) was terminated.
2.32. Drugs interacting with poly ADP-ribose
polymerase (PARP)
Cognitive impairment can be prevented by PARP1 inhibitors administered after hypoglycemia [1578,
1579]. Cognitive and motor deficits were reduced in
mice deficient in PARP-1 [1580].
E-7016 (Eisai following the acquisition of MGI
Pharma, formerly Guilford; presumed to be GPI-21016
under license from Johns Hopkins University, Fig. 22)
is an orally active, brain-penetrable, PARP PAR synthase inhibitor currently in Phase II clinical trials
for the treatment of stage III/IV melanoma patients
[1581]. The indications AD and stroke were abandoned
(Thomson Reuters Pharma, update of June 15,
2012).
MP-124 (Mitsubishi Tanabe Pharma) in a PARP
inhibitor for the potential treatment of acute ischemic
stroke in Phase I clinical trials since December 2008
(Thomson Reuters Pharma, update of February 04,
2011). The structure was not communicated.
AL-309 (Allon Therapeutics), a peptide, is a neuroprotective agent and PARP stimulator in preclinical
studies (Thomson Reuters Pharma, update of May 9,
2012).
2.33. Drugs interacting with prolyl endo peptidase
Several reviews on prolyl endo peptidase, also
known as prolyl oligopeptidase, as a potential target
for the treatment of cognitive disorders were published
[1582–1584]. Sustained efforts over many years have
gone into the discovery and characterization of potent
prolyl endopeptidase inhibitors for the treatment of
592
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
memory disorders [1585]. Potent prolyl endopeptidase
inhibitors, such as KYP-2047 and JTP-4819, did not
increase striatal dopamine, acetylcholine, neurotensin
and substance P levels [1586–1588].
Subchronic administration of rosmarinic acid, a
natural prolyl oligopeptidase inhibitor, enhanced cognitive performances [1589].
The development of many prolyl endopeptidase
inhibitors was terminated, of eurystatin A (BristolMyers Squibb [1590–1593]), JTP-4819 (Japan
Tobacco [1594–1597]), KYP-2047 (Univ. of Kuopio
and Finncovery [1598]), ONO-1603 (Ono Pharmaceuticals [1599, 1600]), S-17092 (Servier [1601–1605])
and S-19825 (Servier [1606]), SUAM-1221 (Chinoin
and sanofi [1598, 1607–1610]), Y-29794 (Yoshitomi, now Mitsubishi Pharma Corp. [1611, 1612]),
Z-321 (Zeria Pharmaceutical [1613–1615]) and ZTTA
[1616].
2.34. Drugs interacting with prostaglandin D & E
synthases
Reviews on the biochemical, structural, genetic,
physiological, and patho-physiological features of
lipocalin-type prostaglandin D synthase were disclosed [1617, 1618]. The three prostaglandin E
synthases were described [1619] as was prostaglandin
E2 synthase inhibition as a therapeutic target [1620]
and the COX-1 mediated prostaglandin E2 elevation
and contextual memory impairment [1621]. Deletion
of microsomal prostaglandin E synthase-1 protected
neuronal cells from the cytotoxic effects of A␤
[1622].
HF-0220 (7-beta-hydroxy-epiandrosterone; Newron Pharmaceuticals; Fig. 22) is a cytoprotective
steroid, which stimulated prostaglandin D synthase
for the potential treatment of AD. A Phase IIa multicenter, double-blind, placebo-controlled, biomarker
trial (NCT00357357) in AD patients was initiated in
April 2007. The randomized, double-blind, placebocontrolled pilot study enrolled 42 patients in the UK,
Sweden, and India. Subjects received 1 to 220 mg/day
of the drug and were allowed to continue with their
current AD treatment. Results were reported in October 2008. HF-0220 was well tolerated at all doses
(Thomson Reuters Pharma, update of August 21,
2012).
AAD-2004 (GNT Pharma, formerly Neurotech and
US subsidiary AmKor, Fig. 22) is a prostaglandin E
synthase-1 inhibitor for the treatment of AD, Parkinson’s disease, and amyotrophic lateral sclerosis. A
Phase I study was initiated in April 2010. By December
2011, the Phase Ia single ascending dose trial had been
successfully completed. In April 2012, it was reported
that a Phase Ib multiple ascending-dose trial to evaluate safety and biomarker profiles was planned for
that year (Thomson Reuters Pharma, update of May 4,
2012).
The development of an analogue of AAD-2004, i.e.,
NG-2006 (GNT Pharma) was terminated.
2.35. Drugs interacting with protein kinase C
Activation of PKC␧ prevents synaptic loss, A␤ elevation, and cognitive deficits in AD transgenic mice
[1623, 1624]. The pharmacology of PKC activators
was extensively reviewed [1625–1629].
APH-0703 (Aphios Corp.), a potent PKC activator, enhanced the generation of non-amyloidogenic,
soluble A␤PP in fibroblasts from AD patients. It
reduced brain amyloid plaques (A␤40 and A␤42 ) in
double-transgenic mice. The drug, formulated using
Aphios’s hydrophobic-based and SFS-PNS polymer
nanospheres technologies, is in Phase II clinical trials
since May 2010 (Thomson Reuters Pharma, update of
July 5, 2012). The structure was not communicated.
Potent activators of PKC are indirect activators of ␣secretase [1630–1632].
Bryostatin-1 (Blanchette Rockefeller Neurosciences Institute) is a naturally occurring PKC
activator isolated from the Californian marine
bryozoan Bugula neritina. In February 2012, the
Institute was preparing to initiate clinical trials in
neurological disorders. Dual effects of bryostatin-1
on spatial memory and depression were described
[1633–1635]. Postischemic PKC activation to rescue
long-term memory was investigated [1636, 1637]. The
chemistry and biology of bryostatins was reviewed
[504] (Thomson Reuters Pharma, update of February
24, 2012). See also Section 2.2. Drugs interacting
with ␣-secretase.
DCP-LA (Hyogo College of Medicine; Fig. 22)
is an activator of PKC␧ for the potential treatment
of stroke and cognitive disorder (Thomson Reuters
Pharma, update of May 25, 2012).
PKC epsilon activators (Blanchette Rockefeller
Neurosciences Institute) are evaluated for the potential treatment of cognitive disorder (Thomson Reuters
Pharma, update of February 17, 2012). The structures
were not communicated.
The development of FR-236924 (Fujisawa, now
Astellas; an activator of PKC␧ [1638–1641]) and of
K-252c (Kyowa Hakko Kogyo; a PKC inhibitor) was
terminated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
593
Fig. 22. A poly ADP-ribose polymerase inhibitor, prostaglandin D and E modulators, a protein kinase C ␧ activator, a Rac1 GTPase inhibitor
and a ras farnesyl transferase inhibitor.
2.36. Drugs interacting with protein tyrosine
phosphatase
The role of striatal-enriched protein tyrosine phosphatase in cognition was described [1642] as was the
involvement of PTPN5, the gene encoding the striatalenriched protein tyrosine phosphatase in schizophrenia
and cognition [1643]. A genome-wide association
study in 700 schizophrenic patients found that three
intronic SNPs in the protein tyrosine phosphatase
receptor type O were associated with learning and
memory [1644]. Knockout mice revealed a role for
protein tyrosine phosphatase in cognition [1645].
LDN-33960 (Yale University) is a striatal-enriched
protein tyrosine phosphatase inhibitor, which
increased the phosphorylation of NMDA receptors
and of ERK in a dose dependent manner. The drug
restored memory in a novel object recognition test in
triple transgenic mice. It appears that the development
of LDN-33960 was terminated (Thomson Reuters
Pharma, update of June 19, 2012).
2.37. Drugs interacting with Rac1 GTPase
The role of Rac1 GTPase in cognitive impairment
following cerebral ischemia in the rat was described
[1646]. The modulation of synaptic function by Rac1
may be a possible link to fragile X syndrome pathology
[1647, 1648].
Cytotoxic Necrotizing Factor 1, a modulator
of Rho GTPases including Rac, Rho, and Cdc42
subfamilies improved object recognition in mice
[1649].
Sanquinarinium chloride (ExonHit; Fig. 22) is an
selective Rac1/1b GTPase nucleotide binding inhibitor
with IC50 ’s of 58 ␮M and 4.6 ␮M for Rac1 and Rac1b,
respectively in nucleotide binding inhibition assays in
preclinical development (Thomson Reuters Pharma,
update of July 20, 2011).
The development of EHT-1864 (EHT-206, EHT101; ExonHit), an orally active small molecule Rac1
GTPase inhibitor capable of crossing the blood brain
barrier was discontinued [1650–1652].
594
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Fig. 23. A S-adenosylhomocysteine hydrolase and a sirtuin inhibitor, a sirtuin activator, a steroid sulfatase and a transglutaminase 2 inhibitor.
2.38. Drugs interacting with Ras Farnesyl
Transferase
Inhibiting farnesylation, but not geranylgeranylation, replicated the enhancement of LTP caused by
simvastatin via the activation of Akt [1653].
LNK-754 (OSI-754, CP-609754; AstraZeneca
following the acquisition of Link Medicine’s neuroscience assets under license from OSI Pharmaceuticals, a subsidiary of Astellas Pharma, and Pfizer;
Fig. 22) is an orally active inhibitor of ras farnesyl
transferase. Two Phase I clinical trials were initiated
in the US, one in May 2009 in 40 healthy elderly
subjects and one in November 2009 in 110 healthy
elderly subjects and in patients with mild AD. Treatment of transgenic mice at 6 months of age for 3 months
showed a clear reduction of plaques caused by either
␣-synuclein or A␤ [1654] (Thomson Reuters Pharma,
update of July 13, 2012).
2.39. Drugs interacting with
S-adenosylhomocysteine hydrolase
Homocysteine potentiated A␤ neurotoxicity [1655].
The S-adenosyl homocysteine hydrolase inhibitor
3-deaza-adenosine prevented cognitive impairment
following folate and vitamin E deprivation in mice
[1656].
L-002259713 (Merck, Fig. 23) is a potent inhibitor
of S-adenosylhomocysteine hydrolase for the potential
treatment of AD. The development was discontinued
(Thomson Reuters Pharma, update of June 19,
2012).
2.40. Drugs interacting with sirtuin
The neuronal protection by sirtuins in AD was
described [1657] as were details on the sirtuin pathway
in aging and AD [1658].
Resveratrol (Fig. 23) is a natural phyto compound,
which activates Sirtuin-1 [1659–1664]. It reduced
A␤ accumulation [1665–1668]. It remodeled soluble oligomers and fibrils of A␤ into off-pathway
conformers [1669]. Resveratrol is not a direct activator of SIRT1 enzyme activity [1670]. Resveratrol
improved memory deficits in mice fed a high-fat diet
[1671]. Subchronic oral toxicity and cardiovascular
safety pharmacology studies were carried out [1672].
The biosynthesis of resveratrol in yeast and in mammalian cells was worked out [1673]. The Georgetown
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
University Medical Center started at Phase II, randomized, double-blind, placebo-controlled study in
patients with mild to moderate AD (expected n = 120)
in the US in May 2012 (NCT015048549). A novel
application in Huntington’s disease was discussed
recently [1674] (Thomson Reuters Pharma, update of
June 22, 2012).
Selisistat (SEN-196, EX-527, SEN-0014196; Siena
Biotech under license from Elixir Pharmaceuticals;
Fig. 23) is a sirtuin-1 inhibitor for the potential
treatment of Huntington’s disease in Phase II trials (PADDINGTON, NCT01485965) in Europe since
April 2011 (Thomson Reuters Pharma, update of May
29, 2012).
INDUS-815C (Indus Biotech) is a natural NADdependent deacetylase sirtuin-2 (SIRT-2) inhibitor
for the potential treatment of Huntington’s disease.
In addition, the drug is evaluated for the potential
treatment of age-related macular degeneration and
retinopathy (Thomson Reuters Pharma, updates of
August 19, 2011 and August 16, 2011, respectively).
The structure was not communicated.
2.41. Drugs interacting with steroid sulfatase
Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder
[1675].
DU-14 (Dusquesne University, Fig. 23) is a
steroid sulfatase inhibitor for the potential enhancement of cognitive function via enhanced levels of
plasma dehydro-epiandrosterone and brain acetylcholine [1676–1679]. Its development was terminated.
2.42. Drugs interacting with transglutaminase
(TG2)
Tissue transglutaminase catalyzes protein crosslinking, an important molecular process in AD.
Accumulation of insoluble proteins with isopeptide
bonds, products of tissue transaminase activity, correlated with cognitive impairment [1680].
CHDI-00339864 (Fig. 23) and CHDI-00316226
(Evotec in collaboration with the CHDI Foundation) are selective TG2 inhibitors (IC50 = 7 nM for
TG2 for CHDI-00316226) for the potential treatment of Huntington’s disease. It displayed an 85
fold greater selectivity for TG2 over Factor XIIIA
(Thomson Reuters Pharma, update of February 10,
2012).
595
2.43. Drugs interacting with ubiquitin
carboxyl-terminal hydroxylase (Usp14)
Inhibitors of this enzyme could accelerate the degradation of neurodegenerative disease-related proteins,
such as tau, TDP-43, and ataxin-3. Changes in hippocampal synaptic transmission were observed in
Usp14-deficient mice [1681].
Usp14 inhibitors (Proteostasis Therapeutics under
license from Harvard University) are investigated for
the potential treatment of neurodegenerative diseases
(Thomson Reuters Pharma, update of August 15,
2012). Structures were not communicated.
3. CONCLUSION
With the launch of donepezil (Aricept) in 1996,
rivastigmine (Exelon) in 2000, and galantamine
(Reminyl) in 2001 (all inhibitors of AChE and
BChE), three valuable medications are available for
the treatment of patients with mild to moderate AD.
Huperzine A was launched in China in 1995, but the
four times a day administration makes it less attractive,
a problem which will be solved by a transdermal patch
currently in Phase I evaluation as XEL-001HP by Xel
Pharmaceuticals.
The development of ten Phase III compounds tested
for the indication AD was terminated, of the AChE
inhibitors amiridin (Nikken), eptastigmine (Mediolanum), metrifonate (Bayer), phenserine (Anonyx),
and velnacrine (HMR, now sanofi), of the ␥-secretase
inhibitors begacestat (Pfizer) and semagacestat (Lilly),
the ␥-secretase modulator tarenflurbil (Myriad Genetics), and of the MAO inhibitors rasagiline (Teva) and
safinamide (Merck Serono).
Currently there is one compound interacting with
enzymes in the pre-registration phase (WIN-026,
WhanIN, an AChE inhibitor), one compound in
Phase III trials (masitinib, AB Science, a kinase
inhibitor), and 15 drugs in Phase II evaluation
(posiphen and Shen Er Yang, two AChE inhibitors),
ladostigil (a dual AChE and MAO inhibitor), etazolate
(an ␣-secretase activator), avagacestat and NIC515 (␥-secretase inhibitors), CHF-5074 (␥-secretase
modulator), tideglusib (GSK-3␤ inhibitor), EVP0334 (HDAC inhibitor), RG-1577 (MAO-B inhibitor),
PF-02545920 (PDE10A inhibitor), rilapladib (PLA2
inhibitor), HF-0220 (prostaglandin D synthase stimulator), APH-0703 (PKC activator), and selisistat
(sirtuin-1 inhibitor).
It may be that positive results will be obtained from
the masitinib Phase III trials within the next two to
596
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
three years, whereas results from the Phase II trials
will be available only within the next five to six years.
[17]
DISCLOSURE STATEMENT
[18]
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1508).
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Giurgea C (1972) [Pharmacology of integrative activity of
the brain. Attempt at nootropic concept in psychopharmacology]. Actual Pharmacol (Paris) 25, 115-156.
Giurgea C (1973) The “nootropic” approach to the pharmacology of the integrative activity of the brain. Cond Reflex
8, 108-115.
Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS,
Clayton NS, Connor R, Davis S, Deakin B, DeRubeis
RJ, Dubois B, Geyer MA, Goodwin GM, Gorwood P, Jay
TM, Joels M, Mansuy IM, Meyer-Lindenberg A, Murphy
D, Rolls E, Saletu B, Spedding M, Sweeney J, Whittington
M, Young LJ (2012) Cognitive dysfunction in psychiatric disorders: Characteristics, causes and the quest for
improved therapy. Nat Rev Drug Discov 11, 141-168.
Froestl W, Maitre L (1989) The families of cognition
enhancers. Pharmacopsychiatry 22(Suppl 2), 54-100.
Froestl W, Muhs A, Pfeifer A (2012) Cognitive enhancers
(nootropics). Part 1: Drugs interacting with receptors.
J Alzheimers Dis, doi: 10.3233/JAD-2012-121186 [Epubl
ahead of print].
Bartus RT, Dean RL III, Beer B, Lippa AS (1982) The
cholinergic hypothesis of geriatric memory dysfunction.
Science 217, 408-414.
Musial A, Bajda M, Malawska B (2007) Recent developments in cholinesterases inhibitors for Alzheimer’s disease
treatment. Curr Med Chem 14, 2654-2679.
Pepeu G, Giovannini MG (2009) Cholinesterase inhibitors
and beyond. Curr Alzheimer Res 6, 86-96.
Pepeu G, Giovannini MG (2010) Cholinesterase inhibitors
and memory. Chem Biol Interact 187, 403-408.
Dumas JA, Newhouse PA (2011) The cholinergic hypothesis of cognitive aging revisited again: Cholinergic
functional compensation. Pharmacol Biochem Behav 99,
254-261.
Schliebs R, Arendt T (2011) The cholinergic system in
aging and neuronal degeneration. Behav Brain Res 221,
555-563.
Terry AV Jr, Callahan PM, Hall B, Webster SJ (2011)
Alzheimer’s disease and age-related memory decline (preclinical). Pharmacol Biochem Behav 99, 190-210.
Speck-Planche A, Luan F, Cordeiro MN (2012) Discovery of anti-Alzheimer agents: Current ligand-based
approaches toward the design of acetylcholinesterase
inhibitors. Mini Rev Med Chem 12, 583-591.
Mehta M, Adem A, Sabbagh M (2012) New acetylcholinesterase inhibitors for Alzheimer’s disease. Int J
Alzheimers Dis 2012, 728983.
Pohanka M (2012) Acetylcholinesterase inhibitors: A
patent review (2008-present). Expert Opin Ther Pat 22,
871-886.
Contestabile A (2011) The history of the cholinergic
hypothesis. Behav Brain Res 221, 334-340.
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
Colombres M, Sagal JP, Inestrosa NC (2004) An overview
of the current and novel drugs for Alzheimer’s disease with
particular reference to anti-cholinesterase compounds.
Curr Pharm Des 10, 3121-3130.
Grutzendler J, Morris JC (2001) Cholinesterase inhibitors
for Alzheimer’s disease. Drugs 61, 41-52.
Sugimoto H, Iimura Y, Yamanishi Y, Yamatsu K (1995)
Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy1-oxoindan-2-yl)methyl]piperidine hydrochloride and
related compounds. J Med Chem 38, 4821-4829.
Kryger G, Silman I, Sussman JL (1998) Threedimensional structure of a complex of E2020 with
acetylcholinesterase from Torpedo californica. J Physiol
Paris 92, 191-194.
Haginaka J, Seyama C (1992) Determination of
enantiomers of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)2-yl]methylpiperidine hydrochloride (E2020), a centrally
acting acetylcholine esterase inhibitor, in plasma by liquid
chromatography with fluorometric detection. J Chromatogr 577, 95-102.
Matsui K, Oda Y, Ohe H, Tanaka S, Asakawa N
(1995) Direct determination of E2020 enantiomers in
plasma by liquid chromatography-mass spectrometry and
column-switching techniques. J Chromatogr A 694, 209218.
Sugimoto H (2008) The new approach in development of
anti-Alzheimer’s disease drugs via the cholinergic hypothesis. Chem Biol Interact 175, 204-208.
Rao RJ, Raol AK, Murthy YL (2007) Efficient and industrially viable synthesis of donepezil. Synth Commun 37,
2847-2853.
Dubey SK, Kharbanda M, Dubey SK, Mathela CS (2010)
A new commercially viable synthetic route for donepezil
hydrochloride: Anti-Alzheimer’s drug. Chem Pharm Bull
(Tokyo) 58, 1157-1160.
Inoue A, Kawai T, Wakita M, Iimura Y, Sugimoto
H, Kawakami Y (1996) The simulated binding of
(+/−)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)4-piperidinyl]meth yl] -1H-inden-1-one hydrochloride
(E2020) and related inhibitors to free and acylated acetylcholinesterases and corresponding structure-activity
analyses. J Med Chem 39, 4460-4470.
Kawakami Y, Inoue A, Kawai T, Wakita M, Sugimoto H,
Hopfinger AJ (1996) The rationale for E2020 as a potent
acetylcholinesterase inhibitor. Bioorg Med Chem 4, 14291446.
Bryson HM, Benfield P (1997) Donepezil. Drugs Aging
10, 234-239.
Heydorn WE (1997) Donepezil (E2020): A new acetylcholinesterase inhibitor. Review of its pharmacology,
pharmacokinetics, and utility in the treatment of
Alzheimer’s disease. Expert Opin Investig Drugs 6, 15271535.
Wilkinson DG (1999) The pharmacology of donepezil: A
new treatment of Alzheimer’s disease. Expert Opin Pharmacother 1, 121-135.
Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J
(2004) Cholinesterase inhibitors used in the treatment of
Alzheimer’s disease: The relationship between pharmacological effects and clinical efficacy. Drugs Aging 21,
453-478.
Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y
(2000) Donepezil hydrochloride (E2020) and other acetylcholinesterase inhibitors. Curr Med Chem 7, 303-339.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
Sugimoto H (2001) Donepezil hydrochloride: A treatment
drug for Alzheimer’s disease. Chem Rec 1, 63-73.
Shigeta M, Homma A (2001) Donepezil for Alzheimer’s
disease: Pharmacodynamic, pharmacokinetic, and clinical
profiles. CNS Drug Rev 7, 353-368.
Seltzer B (2005) Donepezil: A review. Expert Opin Drug
Metab Toxicol 1, 527-536.
Seltzer B (2007) Donepezil: An update. Expert Opin Pharmacother 8, 1011-1023.
Jacobson SA, Sabbagh MN (2008) Donepezil: Potential neuroprotective and disease-modifying effects. Expert
Opin Drug Metab Toxicol 4, 1363-1369.
Kapai NA, Solntseva EI, Skrebitskii VG (2010) Donepezil
eliminates suppressive effects of beta-amyloid peptide
(1–42) on long-term potentiation in the hippocampus. Bull
Exp Biol Med 149, 33-36.
Kapai NA, Bukanova JV, Solntseva EI, Skrebitsky VG
(2012) Donepezil in a narrow concentration range augments control and impaired by beta-amyloid peptide
hippocampal LTP in NMDAR-independent manner. Cell
Mol Neurobiol 32, 219-226.
Freret T, Bouet V, Quiedeville A, Nee G, Dallemagne
P, Rochais C, Boulouard M (2012) Synergistic effect of
acetylcholinesterase inhibition (donepezil) and 5-HT(4)
receptor activation (RS67333) on object recognition in
mice. Behav Brain Res 230, 304-308.
Gomolin IH, Smith C, Jeitner TM (2011) Donepezil dosing
strategies: Pharmacokinetic considerations. J Am Med Dir
Assoc 12, 606-608.
Doody RS (1999) Clinical profile of donepezil in the treatment of Alzheimer’s disease. Gerontology 45(Suppl 1),
23-32.
Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL,
Liao T, Gonzales N, Lai E, Massman P (2001) Chronic
donepezil treatment is associated with slowed cognitive
decline in Alzheimer’s disease. Dement Geriatr Cogn
Disord 12, 295-300.
Doody RS (2003) Current treatments for Alzheimer’s disease: Cholinesterase inhibitors. J Clin Psychiatry 64(Suppl
9), 11-17.
Dooley M, Lamb HM (2000) Donepezil: A review of its
use in Alzheimer’s disease. Drugs Aging 16, 199-226.
Meyer JS, Chowdhury MH, Xu G, Li YS, Quach M (2002)
Donepezil treatment of vascular dementia. Ann N Y Acad
Sci 977, 482-486.
Roman GC, Rogers SJ (2004) Donepezil: A clinical review
of current and emerging indications. Expert Opin Pharmacother 5, 161-180.
Whitehead A, Perdomo C, Pratt RD, Birks J, Wilcock GK,
Evans JG (2004) Donepezil for the symptomatic treatment
of patients with mild to moderate Alzheimer’s disease: A
meta-analysis of individual patient data from randomised
controlled trials. Int J Geriatr Psychiatry 19, 624-633.
Takeda A, Loveman E, Clegg A, Kirby J, Picot J, Payne E,
Green C (2006) A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on
cognition, quality of life and adverse events in Alzheimer’s
disease. Int J Geriatr Psychiatry 21, 17-28.
Hansen RA, Gartlehner G, Webb AP, Morgan LC,
Moore CG, Jonas DE (2008) Efficacy and safety of
donepezil, galantamine, and rivastigmine for the treatment
of Alzheimer’s disease: A systematic review and metaanalysis. Clin Interv Aging 3, 211-225.
Raina P, Santaguida P, Ismaila A, Patterson C, Cowan
D, Levine M, Booker L, Oremus M (2008) Effectiveness
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
597
of cholinesterase inhibitors and memantine for treating
dementia: Evidence review for a clinical practice guideline. Ann Intern Med 148, 379-397.
Sabbagh MN, Richardson S, Relkin N (2008) Diseasemodifying approaches to Alzheimer’s disease: Challenges and opportunities-Lessons from donepezil therapy.
Alzheimers Dement 4, S109-S118.
Rodda J, Morgan S, Walker Z (2009) Are cholinesterase
inhibitors effective in the management of the behavioral and psychological symptoms of dementia in
Alzheimer’s disease? A systematic review of randomized,
placebo-controlled trials of donepezil, rivastigmine and
galantamine. Int Psychogeriatr 21, 813-824.
Tsuno N (2009) Donepezil in the treatment of patients with
Alzheimer’s disease. Expert Rev Neurother 9, 591-598.
Winblad B, Black SE, Homma A, Schwam EM, Moline M,
Xu Y, Perdomo CA, Swartz J, Albert K (2009) Donepezil
treatment in severe Alzheimer’s disease: A pooled analysis
of three clinical trials. Curr Med Res Opin 25, 2577-2587.
Cummings J, Jones R, Wilkinson D, Lopez O, Gauthier
S, Waldemar G, Zhang R, Xu Y, Sun Y, Richardson S,
Mackell J (2010) Effect of donepezil on cognition in severe
Alzheimer’s disease: A pooled data analysis. J Alzheimers
Dis 21, 843-851.
Rosenblatt A, Gao J, Mackell J, Richardson S (2010)
Efficacy and safety of donepezil in patients with
Alzheimer’s disease in assisted living facilities. Am J
Alzheimers Dis Other Demen 25, 483-489.
Santoro A, Siviero P, Minicuci N, Bellavista E, Mishto
M, Olivieri F, Marchegiani F, Chiamenti AM, Benussi L,
Ghidoni R, Nacmias B, Bagnoli S, Ginestroni A, Scarpino
O, Feraco E, Gianni W, Cruciani G, Paganelli R, Di IA,
Scognamiglio M, Grimaldi LM, Gabelli C, Sorbi S, Binetti
G, Crepaldi G, Franceschi C (2010) Effects of donepezil,
galantamine and rivastigmine in 938 Italian patients with
Alzheimer’s disease: A prospective, observational study.
CNS Drugs 24, 163-176.
Lockhart IA, Orme ME, Mitchell SA (2011) The efficacy
of licensed-indication use of donepezil and memantine
monotherapies for treating behavioural and psychological symptoms of dementia in patients with Alzheimer’s
disease: Systematic review and meta-analysis. Dement
Geriatr Cogn Dis Extra 1, 212-227.
Sabbagh M, Cummings J (2011) Progressive cholinergic
decline in Alzheimer’s Disease: Consideration for
treatment with donepezil 23 mg in patients with moderate
to severe symptomatology. BMC Neurol 11, 21.
Waldemar G, Gauthier S, Jones R, Wilkinson D, Cummings J, Lopez O, Zhang R, Xu Y, Sun Y, Knox S,
Richardson S, Mackell J (2011) Effect of donepezil on
emergence of apathy in mild to moderate Alzheimer’s disease. Int J Geriatr Psychiatry 26, 150-157.
Bottini G, Berlingeri M, Basilico S, Passoni S, Danelli L,
Colombo N, Sberna M, Franceschi M, Sterzi R, Paulesu E
(2012) GOOD or BAD responder? Behavioural and neuroanatomical markers of clinical response to donepezil in
dementia. Behav Neurol 25, 61-72.
Doody RS, Geldmacher DS, Farlow MR, Sun Y, Moline
M, Mackell J (2012) Efficacy and safety of donepezil
23 mg versus donepezil 10 mg for moderate-to-severe
Alzheimer’s disease: A subgroup analysis in patients
already taking or not taking concomitant memantine.
Dement Geriatr Cogn Disord 33, 164-173.
Howard R, McShane R, Lindesay J, Ritchie C, Baldwin
A, Barber R, Burns A, Dening T, Findlay D, Holmes
598
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
C, Hughes A, Jacoby R, Jones R, Jones R, McKeith
I, Macharouthu A, O’Brien J, Passmore P, Sheehan B,
Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown
R, Banerjee S, Onions C, Griffin M, Adams J, Gray R,
Johnson T, Bentham P, Phillips P (2012) Donepezil and
memantine for moderate-to-severe Alzheimer’s disease. N
Engl J Med 366, 893-903.
Burke D (2012) Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease.
Ann Intern Med 156, JC6-JC10.
Rodda J, Carter J (2012) Cholinesterase inhibitors and
memantine for symptomatic treatment of dementia. BMJ
344, e2986.
Berk C, Sabbagh M (2012) Broader considerations of
higher doses of donepezil in the treatment of mild, moderate, and severe Alzheimer’s disease. Int J Alzheimers Dis
2012, 707468.
Schwartz LM, Woloshin S (2012) How the FDA forgot the
evidence: The case of donepezil 23 mg. BMJ 344, e1086.
Darreh-Shori T, Soininen H (2010) Effects of
cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid
of patients with Alzheimer’s disease: A review of recent
clinical studies. Curr Alzheimer Res 7, 67-73.
Jackson S, Ham RJ, Wilkinson D (2004) The safety and tolerability of donepezil in patients with Alzheimer’s disease.
Br J Clin Pharmacol 58(Suppl 1), 1-8.
Doody RS, Corey-Bloom J, Zhang R, Li H, Ieni J,
Schindler R (2008) Safety and tolerability of donepezil
at doses up to 20 mg/day: Results from a pilot study in
patients with Alzheimer’s disease. Drugs Aging 25, 163174.
Lockhart IA, Mitchell SA, Kelly S (2009) Safety and tolerability of donepezil, rivastigmine and galantamine for
patients with Alzheimer’s disease: Systematic review of
the ‘real-world’ evidence. Dement Geriatr Cogn Disord
28, 389-403.
Foster RH, Plosker GL (1999) Donepezil. Pharmacoeconomic implications of therapy. Pharmacoeconomics 16,
99-114.
Wolfson C, Oremus M, Shukla V, Momoli F, Demers L,
Perrault A, Moride Y (2002) Donepezil and rivastigmine
in the treatment of Alzheimer’s disease: A best-evidence
synthesis of the published data on their efficacy and costeffectiveness. Clin Ther 24, 862-886.
Wimo A, Winblad B, Engedal K, Soininen H, Verhey
F, Waldemar G, Wetterholm AL, Mastey V, Haglund
A, Zhang R, Miceli R, Chin W, Subbiah P (2003) An
economic evaluation of donepezil in mild to moderate
Alzheimer’s disease: Results of a 1-year, double-blind,
randomized trial. Dement Geriatr Cogn Disord 15,
44-54.
Cappell J, Herrmann N, Cornish S, Lanctot KL (2010) The
pharmacoeconomics of cognitive enhancers in moderate to
severe Alzheimer’s disease. CNS Drugs 24, 909-927.
Getsios D, Blume S, Ishak KJ, Maclaine GD (2010) Cost
effectiveness of donepezil in the treatment of mild to
moderate Alzheimer’s disease: A UK evaluation using
discrete-event simulation. Pharmacoeconomics 28, 411427.
Bond M, Rogers G, Peters J, Anderson R, Hoyle M, Miners
A, Moxham T, Davis S, Thokala P, Wailoo A, Jeffreys M,
Hyde C (2012) The effectiveness and cost-effectiveness
of donepezil, galantamine, rivastigmine and memantine
for the treatment of Alzheimer’s disease (review of Tech-
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
nology Appraisal No. 111): A systematic review and
economic model. Health Technol Assess 16, 1-470.
Versijpt J (2012) Pharmacoeconomics of Alzheimer’s disease (AD) treatment with cholinesterase inhibitors. Acta
Neurol Belg 112, 141-145.
Tricco AC, Soobiah C, Lillie E, Perrier L, Chen MH,
Hemmelgarn B, Majumdar SR, Straus SE (2012) Use of
cognitive enhancers for mild cognitive impairment: Protocol for a systematic review and network meta-analysis.
Syst Rev 1, 25.
Tricco AC, Vandervaart S, Soobiah C, Lillie E, Perrier
L, Straus SE (2012) Efficacy of cognitive enhancers for
Alzheimer’s disease Protocol for a systematic review and
network meta-analysis. Syst Rev 1, 31.
Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone
GT, Spiridigliozzi GA, Heller JH, Richardson S, McRae
T (2009) The efficacy, safety, and tolerability of donepezil
for the treatment of young adults with Down syndrome.
Am J Med Genet A 149A 1641-1654.
Kondoh T, Kanno A, Itoh H, Nakashima M, Honda R,
Kojima M, Noguchi M, Nakane H, Nozaki H, Sasaki H,
Nagai T, Kosaki R, Kakee N, Okuyama T, Fukuda M,
Ikeda M, Shibata Y, Moriuchi H (2011) Donepezil significantly improves abilities in daily lives of female Down
syndrome patients with severe cognitive impairment: A 24week randomized, double-blind, placebo-controlled trial.
Int J Psychiatry Med 41, 71-89.
Kishnani PS, Heller JH, Spiridigliozzi GA, Lott I, Escobar
L, Richardson S, Zhang R, McRae T (2010) Donepezil for
treatment of cognitive dysfunction in children with Down
syndrome aged 10-17. Am J Med Genet A 152A 30283035.
Ravina B, Putt M, Siderowf A, Farrar JT, Gillespie M,
Crawley A, Fernandez HH, Trieschmann MM, Reichwein
S, Simuni T (2005) Donepezil for dementia in Parkinson’s
disease: A randomised, double blind, placebo controlled,
crossover study. J Neurol Neurosurg Psychiatry 76, 934939.
Rowan E, McKeith IG, Saxby BK, O’Brien JT, Burn D,
Mosimann U, Newby J, Daniel S, Sanders J, Wesnes K
(2007) Effects of donepezil on central processing speed
and attentional measures in Parkinson’s disease with
dementia and dementia with Lewy bodies. Dement Geriatr
Cogn Disord 23, 161-167.
van Laar T, De Deyn PP, Aarsland D, Barone P, Galvin JE
(2011) Effects of cholinesterase inhibitors in Parkinson’s
disease dementia: A review of clinical data. CNS Neurosci
Ther 17, 428-441.
Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai
LY, Muenz LR, He D, Benedict RH, Goodman A, Rizvi
S, Schwid SR, Weinstock-Guttman B, Westervelt HJ,
Wishart H (2011) Multicenter randomized clinical trial of
donepezil for memory impairment in multiple sclerosis.
Neurology 76, 1500-1507.
Tariot PN, Farlow MR, Grossberg GT, Graham SM,
McDonald S, Gergel I (2004) Memantine treatment in
patients with moderate to severe Alzheimer disease already
receiving donepezil: A randomized controlled trial. JAMA
291, 317-324.
Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman
JL, Silman I (2002) Kinetic and structural studies on the
interaction of cholinesterases with the anti-Alzheimer drug
rivastigmine. Biochemistry 41, 3555-3564.
Darvesh S, Hopkins DA, Geula C (2003) Neurobiology of
butyrylcholinesterase. Nat Rev Neurosci 4, 131-138.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
[109]
[110]
Amstutz R, Enz A, Marzi M, Boelsterli J, Walkinshaw
M (1990) Cyclische phenylcarbamate des miotin-typs und
ihre wirkung auf die acetylcholinesterase. Helv Chim Acta
73, 739-753.
Boezio AA, Pytkowicz J, Cote A, Charette AB (2003)
Asymmetric, catalytic synthesis of alpha-chiral amines
using a novel bis(phosphine) monoxide chiral ligand.
J Am Chem Soc 125, 14260-14261.
Hu M, Zhang FL, Xie MH (2009) Novel convenient synthesis of rivastigmine. Synth Commun 39, 1527-1533.
Mangas-Sanchez J, Rodriguez-Mata M, Busto E, GotorFernandez V, Gotor V (2009) Chemoenzymatic synthesis
of rivastigmine based on lipase-catalyzed processes. J Org
Chem 74, 5304-5310.
Han K, Kim C, Park J, Kim MJ (2010) Chemoenzymatic
synthesis of rivastigmine via dynamic kinetic resolution as
a key step. J Org Chem 75, 3105-3108.
Enz A, Boddeke H, Gray J, Spiegel R (1991) Pharmacologic and clinicopharmacologic properties of SDZ ENA
713, a centrally selective acetylcholinesterase inhibitor.
Ann N Y Acad Sci 640, 272-275.
Enz A, Amstutz R, Boddeke H, Gmelin G, Malanowski J
(1993) Brain selective inhibition of acetylcholinesterase:
A novel approach to therapy for Alzheimer’s disease. Prog
Brain Res 98, 431-438.
Weinstock M, Razin M, Chorev M, Enz A (1994)
Pharmacological evaluation of phenyl-carbamates as
CNS-selective acetylcholinesterase inhibitors. J Neural
Transm Suppl 43, 219-225.
Gottwald MD, Rozanski RI (1999) Rivastigmine, a brainregion selective acetylcholinesterase inhibitor for treating
Alzheimer’s disease: Review and current status. Expert
Opin Investig Drugs 8, 1673-1682.
Williams BR, Nazarians A, Gill MA (2003) A review of
rivastigmine: A reversible cholinesterase inhibitor. Clin
Ther 25, 1634-1653.
Bailey JA, Ray B, Greig NH, Lahiri DK (2011) Rivastigmine lowers Abeta and increases sAPPalpha levels, which
parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons. PLoS One 6,
e21954.
Polinsky RJ (1998) Clinical pharmacology of rivastigmine: A new-generation acetylcholinesterase inhibitor for
the treatment of Alzheimer’s disease. Clin Ther 20, 634647.
Spencer CM, Noble S (1998) Rivastigmine. A review
of its use in Alzheimer’s disease. Drugs Aging 13, 391411.
Forette F, Anand R, Gharabawi G (1999) A phase II study
in patients with Alzheimer’s disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine
(Exelon). Eur J Neurol 6, 423-429.
Robert P (2002) Understanding and managing behavioural
symptoms in Alzheimer’s disease and related dementias:
Focus on rivastigmine. Curr Med Res Opin 18, 156-171.
Farlow MR (2003) Update on rivastigmine. Neurologist 9,
230-234.
Gabelli C (2003) Rivastigmine: An update on therapeutic
efficacy in Alzheimer’s disease and other conditions. Curr
Med Res Opin 19, 69-82.
Finkel SI (2004) Effects of rivastigmine on behavioral
and psychological symptoms of dementia in Alzheimer’s
disease. Clin Ther 26, 980-990.
Desai AK, Grossberg GT (2005) Rivastigmine for
Alzheimer’s disease. Expert Rev Neurother 5, 563-580.
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
599
Onor ML, Trevisiol M, Aguglia E (2007) Rivastigmine
in the treatment of Alzheimer’s disease: An update. Clin
Interv Aging 2, 17-32.
Trebbastoni A, Gilio F, D’Antonio F, Cambieri C,
Ceccanti M, de LC, Inghilleri M (2012) Chronic treatment
with rivastigmine in patients with Alzheimer’s disease:
A study on primary motor cortex excitability tested by 5
Hz-repetitive transcranial magnetic stimulation. Clin Neurophysiol 123, 902-909.
Emre M, Cummings JL, Lane RM (2007) Rivastigmine in dementia associated with Parkinson’s disease
and Alzheimer’s disease: Similarities and differences.
J Alzheimers Dis 11, 509-519.
Wesnes KA, McKeith I, Edgar C, Emre M, Lane R (2005)
Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 65, 1654-1656.
Wesnes K (2007) Rivastigmine tartrate with a focus
on dementia associated with Parkinson’s disease. Drugs
Today (Barc ) 43, 349-359.
Siddiqui MA, Wagstaff AJ (2006) Rivastigmine: In
Parkinson’s disease dementia. CNS Drugs 20, 739-747.
Siddiqui MA, Wagstaff AJ (2007) Rivastigmine in
Parkinson’s disease dementia: Profile report. Drugs Aging
24, 255-259.
Lalli S, Albanese A (2008) Rivastigmine in Parkinson’s disease dementia. Expert Rev Neurother 8, 11811188.
Almaraz AC, Driver-Dunckley ED, Woodruff BK, Wellik
KE, Caselli RJ, Demaerschalk BM, Adler CH, Caviness
JN, Wingerchuk DM (2009) Efficacy of rivastigmine for
cognitive symptoms in Parkinson disease with dementia.
Neurologist 15, 234-237.
Chitnis S, Rao J (2009) Rivastigmine in Parkinson’s
disease dementia. Expert Opin Drug Metab Toxicol 5,
941-955.
Wesnes KA, McKeith IG, Ferrara R, Emre M, del ST,
Spano PF, Cicin-Sain A, Anand R, Spiegel R (2002)
Effects of rivastigmine on cognitive function in dementia with lewy bodies: A randomised placebo-controlled
international study using the cognitive drug research
computerised assessment system. Dement Geriatr Cogn
Disord 13, 183-192.
Vincent S, Lane R (2003) Rivastigmine in vascular dementia. Int Psychogeriatr 15(Suppl 1), 201-205.
Moretti R, Torre P, Antonello RM, Cazzato G, Bava A
(2004) Rivastigmine in vascular dementia. Expert Opin
Pharmacother 5, 1399-1410.
Craig D, Birks J (2005) Rivastigmine for vascular
cognitive impairment. Cochrane Database Syst Rev 2,
CD004744.
Roman GC (2005) Rivastigmine for subcortical vascular
dementia. Expert Rev Neurother 5, 309-313.
Chapuis C, Casez O, Lagrange E, Bedouch P, Besson
G (2012) Hallucinations treated with rivastigmine in
Creutzfeldt-Jakob disease. Fundam Clin Pharmacol 26,
212-214.
Stryjer R, Ophir D, Bar F, Spivak B, Weizman A, Strous
RD (2012) Rivastigmine treatment for the prevention
of electroconvulsive therapy-induced memory deficits in
patients with schizophrenia 1. Clin Neuropharmacol 35,
161-164.
Darreh-Shori T, Jelic V (2010) Safety and tolerability of
transdermal and oral rivastigmine in Alzheimer’s disease
and Parkinson’s disease dementia. Expert Opin Drug Saf
9, 167-176.
600
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Lamb HM, Goa KL (2001) Rivastigmine. A pharmacoeconomic review of its use in Alzheimer’s disease.
Pharmacoeconomics 19, 303-318.
Cummings J, Winblad B (2007) A rivastigmine patch
for the treatment of Alzheimer’s disease and Parkinson’s disease dementia. Expert Rev Neurother 7, 14571463.
Yang LP, Keating GM (2007) Rivastigmine transdermal
patch: In the treatment of dementia of the Alzheimer’s
type. CNS Drugs 21, 957-965.
Winblad B, Machado JC (2008) Use of rivastigmine transdermal patch in the treatment of Alzheimer’s disease.
Expert Opin Drug Deliv 5, 1377-1386.
Kurz A, Farlow M, Lefevre G (2009) Pharmacokinetics of
a novel transdermal rivastigmine patch for the treatment of
Alzheimer’s disease: A review. Int J Clin Pract 63, 799805.
Cummings JL, Ferris SH, Farlow MR, Olin JT, Meng X
(2010) Effects of rivastigmine transdermal patch and capsule on aspects of clinical global impression of change
in Alzheimer’s disease: A retrospective analysis. Dement
Geriatr Cogn Disord 29, 406-412.
Emre M, Bernabei R, Blesa R, Bullock R, Cunha
L, Daniels H, Dziadulewicz E, Forstl H, Frolich L,
Gabryelewicz T, Levin O, Lindesay J, Martinez-Lage P,
Monsch A, Tsolaki M, van LT (2010) Drug profile: Transdermal rivastigmine patch in the treatment of Alzheimer
disease. CNS Neurosci Ther 16, 246-253.
Farlow MR, Alva G, Meng X, Olin JT (2010) A 25-week,
open-label trial investigating rivastigmine transdermal
patches with concomitant memantine in mild-to-moderate
Alzheimer’s disease: A post hoc analysis. Curr Med Res
Opin 26, 263-269.
Farlow MR, Grossberg GT, Meng X, Olin J, Somogyi
M (2011) Rivastigmine transdermal patch and capsule
in Alzheimer’s disease: Influence of disease stage on
response to therapy. Int J Geriatr Psychiatry 26, 12361243.
Farlow MR, Grossberg GT, Meng X, Olin J, Somogyi
M (2011) Rivastigmine transdermal patch and capsule
in Alzheimer’s disease: Influence of disease stage on
response to therapy. Int J Geriatr Psychiatry 26, 12361243.
Grossberg GT, Sadowsky C, Olin JT (2010) Rivastigmine
transdermal system for the treatment of mild to moderate
Alzheimer’s disease. Int J Clin Pract 64, 651-660.
Grossberg GT, Schmitt FA, Meng X, Tekin S, Olin J (2010)
Reviews: Effects of transdermal rivastigmine on ADAScog items in mild-to-moderate Alzheimer’s disease. Am J
Alzheimers Dis Other Demen 25, 627-633.
Grossberg GT, Olin JT, Somogyi M, Meng X (2011) Dose
effects associated with rivastigmine transdermal patch in
patients with mild-to-moderate Alzheimer’s disease. Int J
Clin Pract 65, 465-471.
Sadowsky CH, Dengiz A, Meng X, Olin JT (2010)
Switching from oral donepezil to rivastigmine transdermal
patch in Alzheimer’s disease: 20-week extension phase
results. Prim Care Companion J Clin Psychiatry 12, pii:
PCC.09m00852.
Sadowsky CH, Grossberg GT, Somogyi M, Meng X (2011)
Predictors of sustained response to rivastigmine in patients
with Alzheimer’s disease: A retrospective analysis. Prim
Care Companion CNS Disord 13, pii: PCC.10m01101
Alva G, Grossberg GT, Schmitt FA, Meng X, Olin JT
(2011) Efficacy of rivastigmine transdermal patch on activ-
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
ities of daily living: Item responder analyses. Int J Geriatr
Psychiatry 26, 356-363.
Articus K, Baier M, Tracik F, Kuhn F, Preuss UW, Kurz
A (2011) A 24-week, multicentre, open evaluation of the
clinical effectiveness of the rivastigmine patch in patients
with probable Alzheimer’s disease. Int J Clin Pract 65,
790-796.
Choi SH, Park KW, Na DL, Han HJ, Kim EJ, Shim YS,
Lee JH (2011) Tolerability and efficacy of memantine addon therapy to rivastigmine transdermal patches in mild to
moderate Alzheimer’s disease: A multicenter, randomized,
open-label, parallel-group study. Curr Med Res Opin 27,
1375-1383.
Dhillon S (2011) Spotlight on rivastigmine transdermal
patchdagger: In dementia of the Alzheimer’s type. Drugs
Aging 28, 927-930.
Dhillon S (2011) Rivastigmine transdermal patch: A
review of its use in the management of dementia of the
Alzheimer’s type. Drugs 71, 1209-1231.
Greenspoon J, Herrmann N, Adam DN (2011) Transdermal rivastigmine: Management of cutaneous adverse
events and review of the literature. CNS Drugs 25, 575583.
Han HJ, Lee JJ, Park SA, Park HY, Kim JE, Shim
YS, Shim DS, Kim EJ, Yoon SJ, Choi SH (2011) Efficacy and safety of switching from oral cholinesterase
inhibitors to the rivastigmine transdermal patch in patients
with probable Alzheimer’s disease. J Clin Neurol 7, 137142.
Nagy B, Brennan A, Brandtmuller A, Thomas SK, Sullivan
SD, Akehurst R (2011) Assessing the cost-effectiveness
of the rivastigmine transdermal patch for Alzheimer’s disease in the UK using. Int J Geriatr Psychiatry 26, 483494.
Weintraub D, Somogyi M, Meng X (2011) Rivastigmine
in Alzheimer’s disease and Parkinson’s disease dementia:
An ADAS-Cog factor analysis. Am J Alzheimers Dis Other
Demen 26, 443-449.
Seibert J, Tracik F, Articus K, Spittler S (2012) Effectiveness and tolerability of transdermal rivastigmine in the
treatment of Alzheimer’s disease in daily practice. Neuropsychiatr Dis Treat 8, 141-147.
Tian H, Abouzaid S, Chen W, Kahler KH, Kim E
(2012) Patient adherence to transdermal rivastigmine
after switching from oral donepezil: A retrospective
claims database study. Alzheimer Dis Assoc Disord, doi:
10.1097/WAD.0b013e318266fb02 [Epubl ahead of print].
Raskind MA (2003) Update on Alzheimer drugs (galantamine). Neurologist 9, 235-240.
Stanilova MI, Molle ED, Yanev SG (2010) Galanthamine
production by Leucojum aestivum cultures in vitro. Alkaloids Chem Biol 68, 167-270.
Ivanov I, Georgiev V, Georgiev M, Ilieva M, Pavlov A
(2011) Galanthamine and related alkaloids production
by Leucojum aestivum L. shoot culture using a temporary immersion technology. Appl Biochem Biotechnol 163,
268-277.
Küenburg B, Czollner L, Fröhlich J, Jordis U (1999) Development of a pilot scale process for the anti-Alzheimer drug
(-)-galanthamine using large-scale phenolic oxidative coupling and crystallization-induced chiral conversion. Org
Process Res Development 3, 425-431.
Trost BM, Tang W, Toste FD (2005) Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine. J
Am Chem Soc 127, 14785-14803.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[160]
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179]
Satcharoen V, McLean NJ, Kemp SC, Camp NP, Brown RC
(2007) Stereocontrolled synthesis of (−)-galanthamine.
Org Lett 9, 1867-1869.
Tanimoto H, Kato T, Chida N (2007) Total synthesis of (+)galanthamine starting from D-glucose. Tetrahedron Lett
48, 6267-6270.
Reddy JM, Kumar KV, Raju V, Bhaskar BV, Himabindu
V, Bhattacharya A, Sundaram A, Banerjee R, Reddy
GM, Bandichhor R (2008) Alternative total synthesis of
(-)-galanthamine hydrobromide. Synth Commun 38, 21382149.
Chang JH, Kang HU, Jung IH, Cho CG (2010) Total
synthesis of (+/−)-galanthamine via a C3-selective Stille
coupling and IMDA cycloaddition cascade of 3,5dibromo-2-pyrone. Org Lett 12, 2016-2018.
Harvey AL (1995) The pharmacology of galanthamine and
its analogues. Pharmacol Ther 68, 113-128.
Fulton B, Benfield P (1996) Galanthamine. Drugs Aging
9, 60-65.
Blesa R (2000) Galantamine: Therapeutic effects beyond
cognition. Dement Geriatr Cogn Disord 11(Suppl 1), 2834.
Sramek JJ, Frackiewicz EJ, Cutler NR (2000) Review
of the acetylcholinesterase inhibitor galanthamine. Expert
Opin Investig Drugs 9, 2393-2402.
Pearson VE (2001) Galantamine: A new alzheimer
drug with a past life. Ann Pharmacother 35, 14061413.
Marco L, do Carmo Carreiras M (2006) Galanthamine, a
natural product for the treatment of Alzheimer’s disease.
Recent Pat CNS Drug Discov 1, 105-111.
Marco-Contelles J, do Carmo Carreiras M, Rodriguez C,
Villarroya M, Garcia AG (2006) Synthesis and pharmacology of galantamine. Chem Rev 106, 116-133.
Van Dam D, De Deyn PP (2006) Cognitive evaluation of
disease-modifying efficacy of galantamine and memantine
in the APP23 model. Eur Neuropsychopharmacol 16, 5969.
Villarroya M, Garcia AG, Marco-Contelles J, Lopez MG
(2007) An update on the pharmacology of galantamine.
Expert Opin Investig Drugs 16, 1987-1998.
Matharu B, Gibson G, Parsons R, Huckerby TN, Moore
SA, Cooper LJ, Millichamp R, Allsop D, Austen B (2009)
Galantamine inhibits beta-amyloid aggregation and cytotoxicity. J Neurol Sci 280, 49-58.
Prvulovic D, Hampel H, Pantel J (2010) Galantamine for
Alzheimer’s disease. Expert Opin Drug Metab Toxicol 6,
345-354.
Ago Y, Koda K, Takuma K, Matsuda T (2011) Pharmacological aspects of the acetylcholinesterase inhibitor
galantamine. J Pharmacol Sci 116, 6-17.
Vigneault P, Bourgault S, Kaddar N, Caillier B, Pilote
S, Patoine D, Simard C, Drolet B (2012) Galantamine
(Reminyl(R)) delays cardiac ventricular repolarization and
prolongs the QT interval by blocking the HERG current.
Eur J Pharmacol 681, 68-74.
Maelicke A (2000) Allosteric modulation of nicotinic
receptors as a treatment strategy for Alzheimer’s disease.
Dement Geriatr Cogn Disord 11(Suppl 1), 11-18.
Maelicke A, Schrattenholz A, Samochocki M, Radina M,
Albuquerque EX (2000) Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for
Alzheimer’s disease. Behav Brain Res 113, 199-206.
Maelicke A, Samochocki M, Jostock R, Fehrenbacher A,
Ludwig J, Albuquerque EX, Zerlin M (2001) Allosteric
[180]
[181]
[182]
[183]
[184]
[185]
[186]
[187]
[188]
[189]
[190]
[191]
[192]
[193]
[194]
[195]
[196]
[197]
601
sensitization of nicotinic receptors by galantamine, a new
treatment strategy for Alzheimer’s disease. Biol Psychiatry
49, 279-288.
Coyle J, Kershaw P (2001) Galantamine, a cholinesterase
inhibitor that allosterically modulates nicotinic receptors:
Effects on the course of Alzheimer’s disease. Biol Psychiatry 49, 289-299.
Woodruff-Pak DS, Lander C, Geerts H (2002) Nicotinic
cholinergic modulation: Galantamine as a prototype. CNS
Drug Rev 8, 405-426.
Alexander KS, Wu HQ, Schwarcz R, Bruno JP (2012)
Acute elevations of brain kynurenic acid impair cognitive
flexibility: Normalization by the alpha7 positive modulator galantamine. Psychopharmacology (Berl) 220, 627637.
Bickel U, Thomsen T, Weber W, Fischer JP, Bachus R, Nitz
M, Kewitz H (1991) Pharmacokinetics of galanthamine in
humans and corresponding cholinesterase inhibition. Clin
Pharmacol Ther 50, 420-428.
Farlow MR (2003) Clinical pharmacokinetics of galantamine. Clin Pharmacokinet 42, 1383-1392.
Monbaliu J, Verhaeghe T, Willems B, Bode W, Lavrijsen K, Meuldermans W (2003) Pharmacokinetics of
galantamine, a cholinesterase inhibitor, in several animal
species. Arzneimittelforschung 53, 486-495.
van Beijsterveldt L, Geerts R, Verhaeghe T, Willems
B, Bode W, Lavrijsen K, Meuldermans W (2004) Pharmacokinetics and tissue distribution of galantamine and
galantamine-related radioactivity after single intravenous
and oral administration in the rat. Arzneimittelforschung
54, 85-94.
Huang F, Fu Y (2010) A review of clinical pharmacokinetics and pharmacodynamics of galantamine, a
reversible acetylcholinesterase inhibitor for the treatment
of Alzheimer’s disease, in healthy subjects and patients.
Curr Clin Pharmacol 5, 115-124.
Rainer M (1997) Galanthamine in Alzheimer’s disease. A
new alternative to tacrine? CNS Drugs 7, 89-97.
Scott LJ , Goa KL (2000) Galantamine: A review of its use
in Alzheimer’s disease. Drugs 60, 1095-1122.
Tariot P (2001) Current status and new developments
with galantamine in the treatment of Alzheimer’s disease.
Expert Opin Pharmacother 2, 2027-2049.
Erkinjuntti T (2002) Broad therapeutic benefits in patients
with probable vascular dementia or Alzheimer’s disease
with cerebrovascular disease after treatment with galantamine. Eur J Neurol 9, 545.
Kurz A (2002) A novel treatment for patients with
Alzheimer’s disease and with vascular dementia. Ann
N Y Acad Sci 977, 476-481.
Lilienfeld S (2002) Galantamine–a novel cholinergic drug
with a unique dual mode of action for the treatment of
patients with Alzheimer’s disease. CNS Drug Rev 8, 159176.
Corey-Bloom J (2003) Galantamine: A review of its use
in Alzheimer’s disease and vascular dementia. Int J Clin
Pract 57, 219-223.
Zarotsky V, Sramek JJ, Cutler NR (2003) Galantamine
hydrobromide: An agent for Alzheimer’s disease. Am J
Health Syst Pharm 60, 446-452.
Bullock R (2004) Galantamine: Use in Alzheimer’s disease and related disorders. Expert Rev Neurother 4,
153-163.
Robinson DM, Plosker GL (2006) Galantamine extended
release. CNS Drugs 20, 673-681.
602
[198]
[199]
[200]
[201]
[201]
[202]
[203]
[204]
[205]
[206]
[207]
[208]
[209]
[210]
[211]
[212]
[213]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Seltzer B (2010) Galantamine-ER for the treatment of
mild-to-moderate Alzheimer’s disease. Clin Interv Aging
5, 1-6.
Kavanagh S, Gaudig M, Van Baelen B, Adami M, Delgado
A, Guzman C, Jedenius E, Schauble B (2011) Galantamine
and behavior in Alzheimer disease: Analysis of four trials.
Acta Neurol Scand 124, 302-308.
Wallin AK, Wattmo C, Minthon L (2011) Galantamine
treatment in Alzheimer’s disease: Response and long-term
outcome in a routine clinical setting. Neuropsychiatr Dis
Treat 7, 565-576.
Aarsland D, Hutchinson M, Larsen JP (2003) Cognitive,
psychiatric and motor response to galantamine in Parkinson’s disease with dementia. Int J Geriatr Psychiatry 18,
937-941.
[1]Scarpini E, Bruno G, Zappala G, Adami M, Richarz U,
Gaudig M, Jacobs A, Schauble B (2011) Cessation versus
continuation of galantamine treatment after 12 months of
therapy in patients with Alzheimer’s disease: a randomized, double blind, placebo controlled withdrawal trial. J
Alzheimers Dis 26, 211-220.
Bora E, Veznedaroglu B, Kayahan B (2005) The effect
of galantamine added to clozapine on cognition of five
patients with schizophrenia. Clin Neuropharmacol 28,
139-141.
Craig D, Birks J (2006) Galantamine for vascular cognitive
impairment. Cochrane Database Syst Rev, CD004746.
Caro JJ, Salas M, Ward A, Getsios D, Mehnert A
(2002) Economic analysis of galantamine, a cholinesterase
inhibitor, in the treatment of patients with mild to moderate
Alzheimer’s disease in the Netherlands. Dement Geriatr
Cogn Disord 14, 84-89.
Heinrich M (2010) Galanthamine from Galanthus and
other Amaryllidaceae–chemistry and biology based on traditional use. Alkaloids Chem Biol 68, 157-165.
Maelicke A, Hoeffle-Maas A, Ludwig J, Maus A, Samochocki M, Jordis U, Koepke AK (2010) Memogain
is a galantamine pro-drug having dramatically reduced
adverse effects and enhanced efficacy. J Mol Neurosci 40,
135-137.
Hirasawa Y, Kobayashi J, Morita H (2009) The
Lycopodium alkaloids. Heterocycles 77, 679-729.
Bai DL, Tang XC, He XC (2000) Huperzine A, a potential therapeutic agent for treatment of Alzheimer’s disease.
Curr Med Chem 7, 355-374.
Wang R, Yan H, Tang XC (2006) Progress in studies of
huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 27, 1-26.
Saxena A, Qian N, Kovach IM, Kozikowski AP, Pang
YP, Vellom DC, Radic Z, Quinn D, Taylor P, Doctor BP
(1994) Identification of amino acid residues involved in
the binding of Huperzine A to cholinesterases. Protein Sci
3, 1770-1778.
McKinney M, Miller JH, Yamada F, Tuckmantel W,
Kozikowski AP (1991) Potencies and stereoselectivities
of enantiomers of huperzine A for inhibition of rat cortical acetylcholinesterase. Eur J Pharmacol 203, 303305.
Pang YP, Kozikowski AP (1994) Prediction of the binding
sites of huperzine A in acetylcholinesterase by docking
studies. J Comput Aided Mol Des 8, 669-681.
Ashani Y, Grunwald J, Kronman C, Velan B, Shafferman
A (1994) Role of tyrosine 337 in the binding of huperzine
A to the active site of human acetylcholinesterase. Mol
Pharmacol 45, 555-560.
[214]
[215]
[216]
[217]
[218]
[219]
[220]
[221]
[222]
[223]
[224]
[225]
[226]
[227]
[228]
[229]
[230]
[231]
Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He
XC, Jin GY, Yu GL, Tang XC, Silman I, Bai DL, Sussman JL (2002) X-ray structures of Torpedo californica
acetylcholinesterase complexed with (+)-huperzine A and
(−)-huperzine B: Structural evidence for an active site
rearrangement. Biochemistry 41, 10810-10818.
Ma X, Gang DR (2008) In vitro production of huperzine
A, a promising drug candidate for Alzheimer’s disease.
Phytochemistry 69, 2022-2028.
Xia Y, Kozikowski AP (1989) A practical synthesis of the
Chinese nootropic agent Huperzine A: A possible lead in
the treatment of Alzheimer’s disease. J Amer Chem Soc
111, 4116-4117.
Campiani G, Sun LQ, Kozikowski AP, Aagaard P,
McKinney M (1993) A palladium-catalyzed route to
Huperzine A and its analogues and their anticholesterase
activity. J Org Chem 58, 7660-7669.
Kaneko S, Yoshino T, Katoh T, Terashima S (1998) Synthetic studies of huperzine A and its fluorinated analogs.
1. Novel asymmetric syntheses of an enantiomeric pair of
Huperazine A. Tetrahedron 54, 5471-5484.
Kelly SA, Foricher Y, Mann J, Bentley JM (2003) A
convergent approach to huperzine A and analogues. Org
Biomol Chem 1, 2865-2876.
Lucey C, Kelly SA, Mann J (2007) A concise and convergent (formal) total synthesis of huperzine A. Org Biomol
Chem 5, 301-306.
Koshiba T, Yokoshima S, Fukuyama T (2009) Total synthesis of (−)-huperzine A. Org Lett 11, 5354-5356.
Ding R, Sun BF, Lin GQ (2012) An efficient total synthesis
of (−)-huperzine A. Org Lett 14, 4446-4449.
Tudhope SR, Bellamy JA, Ball A, Rajasekar D, AzadiArdakani M, Meera HS, Gnanadeepam JM, Saiganesh R,
Gibson F, He L, Behrens CH, Underiner G, Marturt J, Favre
N (2012) Development of a large-scale synthetic route to
manufacture (−)-Huperzine A. Org Process Res Dev 16,
635-642.
Cheng DH, Ren H, Tang XC (1996) Huperzine A, a novel
promising acetylcholinesterase inhibitor. Neuroreport 8,
97-101.
Zangara A (2003) The psychopharmacology of huperzine
A: An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s
disease. Pharmacol Biochem Behav 75, 675-686.
Wang R, Yan H, Tang XC (2006) Progress in studies of
huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 27, 1-26.
Zhang HY, Tang XC (2006) Neuroprotective effects of
huperzine A: New therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci 27, 619-625.
Zhang HY, Zheng CY, Yan H, Wang ZF, Tang LL, Gao X,
Tang XC (2008) Potential therapeutic targets of huperzine
A for Alzheimer’s disease and vascular dementia. Chem
Biol Interact 175, 396-402.
Zhang HY, Yan H, Tang XC (2008) Non-cholinergic
effects of huperzine A: Beyond inhibition of acetylcholinesterase. Cell Mol Neurobiol 28, 173-183.
Ha GT, Wong RK, Zhang Y (2011) Huperzine a as potential
treatment of Alzheimer’s disease: An assessment on chemistry, pharmacology, and clinical studies. Chem Biodivers
8, 1189-1204.
Wang R, Zhang HY, Tang XC (2001) Huperzine A attenuates cognitive dysfunction and neuronal degeneration
caused by beta-amyloid protein-(1-40) in rat 20. Eur J
Pharmacol 421, 149-156.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[232]
[233]
[234]
[235]
[236]
[237]
[238]
[239]
[240]
[241]
[242]
[243]
[244]
[245]
Xiao XQ, Zhang HY, Tang XC (2002) Huperzine A
attenuates amyloid beta-peptide fragment 25-35-induced
apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. J Neurosci
Res 67, 30-36.
Zhang HY, Liang YQ, Tang XC, He XC, Bai DL (2002)
Stereoselectivities of enantiomers of huperzine A in protection against beta-amyloid(25-35)-induced injury in
PC12 and NG108-15 cells and cholinesterase inhibition
in mice. Neurosci Lett 317, 143-146.
Gao X, Tang XC (2006) Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC12 cells by
reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism. J Neurosci Res 83,
1048-1057.
Gao X, Zheng CY, Yang L, Tang XC, Zhang HY (2009)
Huperzine A protects isolated rat brain mitochondria
against beta-amyloid peptide. Free Radic Biol Med 46,
1454-1462.
Zhang HY, Yan H, Tang XC (2004) Huperzine A enhances
the level of secretory amyloid precursor protein and protein
kinase C-alpha in intracerebroventricular beta-amyloid-(140) infused rats and human embryonic kidney 293 Swedish
mutant cells. Neurosci Lett 360, 21-24.
Yan H, Zhang HY, Tang XC (2007) Involvement of M1muscarinic acetylcholine receptors, protein kinase C and
mitogen-activated protein kinase in the effect of huperzine
A on secretory amyloid precursor protein-alpha. Neuroreport 18, 689-692.
Peng Y, Jiang L, Lee DY, Schachter SC, Ma Z, Lemere
CA (2006) Effects of huperzine A on amyloid precursor
protein processing and beta-amyloid generation in human
embryonic kidney 293 APP Swedish mutant cells. J Neurosci Res 84, 903-911.
Peng Y, Lee DY, Jiang L, Ma Z, Schachter SC, Lemere
CA (2007) Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated
protein kinase pathways in neuroblastoma SK-N-SH cells
over-expressing wild type human amyloid precursor protein 695. Neuroscience 150, 386-395.
Wang CY, Zheng W, Wang T, Xie JW, Wang SL,
Zhao BL, Teng WP, Wang ZY (2011) Huperzine A
activates Wnt/beta-catenin signaling and enhances the
nonamyloidogenic pathway in an Alzheimer transgenic
mouse model. Neuropsychopharmacology 36, 10731089.
Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero
D, Perez B, Clos MV, Badia A (2012) Huprine X and
huperzine A improve cognition and regulate some neurochemical processes related with alzheimer’s disease in
triple transgenic mice (3xTg-AD). Neurodegener Dis, doi:
10.1159/000336427 [Epubl ahead of print].
Little JT, Walsh S, Aisen PS (2008) An update on huperzine
A as a treatment for Alzheimer’s disease. Expert Opin
Investig Drugs 17, 209-215.
Desilets AR, Gickas JJ, Dunican KC (2009) Role of
huperzine a in the treatment of Alzheimer’s disease. Ann
Pharmacother 43, 514-518.
Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ
(2009) Efficacy and safety of natural acetylcholinesterase
inhibitor huperzine A in the treatment of Alzheimer’s
disease: An updated meta-analysis. J Neural Transm 116,
457-465.
Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward
C, Jin S, Thomas R, Aisen PS (2011) A phase II trial
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
[256]
[257]
[258]
[259]
603
of huperzine A in mild to moderate Alzheimer disease.
Neurology 76, 1389-1394.
Hogenauer K, Baumann K, Enz A, Mulzer J (2001) Synthesis and acetylcholinesterase inhibition of 5-desamino
huperzine A derivatives. Bioorg Med Chem Lett 11, 26272630.
Park SJ, Jung HJ, Son MS, Jung JM, Kim DH, Jung IH,
Cho YB, Lee EH, Ryu JH (2012) Neuroprotective effects
of INM-176 against lipopolysaccharide-induced neuronal
injury. Pharmacol Biochem Behav 101, 427-433.
Park SJ, Jung JM, Lee HE, Lee YW, Kim DH, Kim JM,
Hong JG, Lee CH, Jung IH, Cho YB, Jang DS, Ryu JH
(2012) The memory ameliorating effects of INM-176, an
ethanolic extract of Angelica gigas, against scopolamineor Abeta(1-42)-induced cognitive dysfunction in mice. J
Ethnopharmacol 143, 611-620.
Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS,
Utsuki T, Giordano T, Sambamurti K, Greig NH (2007)
The experimental Alzheimer’s disease drug posiphen [(+)phenserine] lowers amyloid-beta peptide levels in cell
culture and mice. J Pharmacol Exp Ther 320, 386-396.
Rogers JT, Mikkilineni S, Cantuti-Castelvetri I, Smith DH,
Huang X, Bandyopadhyay S, Cahill CM, Maccecchini
ML, Lahiri DK, Greig NH (2011) The alpha-synuclein
5’untranslated region targeted translation blockers: Antialpha synuclein efficacy of cardiac glycosides and
Posiphen. J Neural Transm 118, 493-507.
Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier
A, Greig NH, Rogers JT (2012) The anticholinesterase
phenserine and its enantiomer posiphen as 5 untranslatedregion-directed translation blockers of the Parkinson’s
alpha synuclein expression. Parkinsons Dis 2012,
142372.
Maccecchini ML, Chang MY, Pan C, John V, Zetterberg
H, Greig NH (2012) Posiphen as a candidate drug to lower
CSF amyloid precursor protein, amyloid-beta peptide and
tau levels: Target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry 83,
894-902.
Pavlic M (1970) The inhibition of butyrylcholinesterase
by methanesulfonyl fluoride. Biochim Biophys Acta 198,
389-391.
Krupka RM (1974) Methanesulfonyl fluoride inactivation of acetylcholinesterase in the presence of substrates
and reversible inhibitors. Biochim Biophys Acta 370,
197-207.
Malin DH, Toups PJ, Osgood LD, Fowler DE, Hunter
CL, Arcangeli KR, Moss DE (1991) Methanesulfonyl fluoride enhances one-trial reward learning in mid-aged rats.
Neurobiol Aging 12, 181-183.
Malin DH, Plotner RE, Radulescu SJ, Ferebee RN, Lake
JR, Negrete PG, Schaefer PJ, Crothers MK, Moss DE
(1993) Chronic methanesulfonyl fluoride enhances onetrial per day reward learning in aged rats. Neurobiol Aging
14, 393-395.
Palacios-Esquivel RL, Pacheco G, Moss DE (1993)
Methanesulfonyl fluoride (MSF) blocks scopolamineinduced amnesia in rats. Neurobiol Aging 14, 93-96.
Borlongan CV, Sumaya IC, Moss DE (2005) Methanesulfonyl fluoride, an acetylcholinesterase inhibitor, attenuates
simple learning and memory deficits in ischemic rats.
Brain Res 1038, 50-58.
Moss DE, Berlanga P, Hagan MM, Sandoval H, Ishida C
(1999) Methanesulfonyl fluoride (MSF): A double-blind,
placebo-controlled study of safety and efficacy in the treat-
604
[260]
[261]
[262]
[263]
[264]
[265]
[266]
[267]
[268]
[269]
[270]
[271]
[272]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
ment of senile dementia of the Alzheimer type. Alzheimer
Dis Assoc Disord 13, 20-25.
Kamal MA, Klein P, Yu QS, Tweedie D, Li Y, Holloway
HW, Greig NH (2006) Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental
Alzheimer therapeutic, bisnorcymserine. J Alzheimers Dis
10, 43-51.
Bartolucci C, Stojan J, Yu QS, Greig NH, Lamba D (2012)
Kinetics of Torpedo californica acetylcholinesterase inhibition by bisnorcymserine and crystal structure of the
complex with its leaving group. Biochem J 444, 269-277.
Pang YP, Quiram P, Jelacic T, Hong F, Brimijoin S
(1996) Highly potent, selective, and low cost bistetrahydroaminacrine inhibitors of acetylcholinesterase.
Steps toward novel drugs for treating Alzheimer’s disease.
J Biol Chem 271, 23646-23649.
Wang ZF, Yan J, Fu Y, Tang XC, Feng S, He XC, Bai
DL (2008) Pharmacodynamic study of FS-0311: A novel
highly potent, selective acetylcholinesterase inhibitor. Cell
Mol Neurobiol 28, 245-261.
Badia A, Banos JE, Camps P, Contreras J, Gorbig DM,
Munoz-Torrero D, Simon M, Vivas NM (1998) Synthesis and evaluation of tacrine-huperzine A hybrids as
acetylcholinesterase inhibitors of potential interest for the
treatment of Alzheimer’s disease. Bioorg Med Chem 6,
427-440.
Camps P, El AR, Gorbig DM, Morral J, Munoz-Torrero D,
Badia A, Eladi BJ, Vivas NM, Barril X, Orozco M, Luque
FJ (1999) Synthesis, in vitro pharmacology, and molecular
modeling of very potent tacrine-huperzine A hybrids as
acetylcholinesterase inhibitors of potential interest for the
treatment of Alzheimer’s disease. J Med Chem 42, 32273242.
Camps P, Cusack B, Mallender WD, El Achab RE, Morral
J, Munoz-Torrero D, Rosenberry TL (2000) Huprine X is
a novel high-affinity inhibitor of acetylcholinesterase that
is of interest for treatment of Alzheimer’s disease. Mol
Pharmacol 57, 409-417.
Camps P, El AR, Morral J, Munoz-Torrero D, Badia
A, Banos JE, Vivas NM, Barril X, Orozco M, Luque
FJ (2000) New tacrine-huperzine A hybrids (huprines):
Highly potent tight-binding acetylcholinesterase inhibitors
of interest for the treatment of Alzheimer’s disease. J Med
Chem 43, 4657-4666.
Camps P, Gomez E, Munoz-Torrero D, Badia A, Vivas
NM, Barril X, Orozco M, Luque FJ (2001) Synthesis,
in vitro pharmacology, and molecular modeling of synhuprines as acetylcholinesterase inhibitors. J Med Chem
44, 4733-4736.
Camps P, Munoz-Torrero D (2001) Tacrine-huperzine A
hybrids (huprines): A new class of highly potent and
selective acetylcholinesterase inhibitors of interest for the
treatment of Alzheimer’s disease. Mini Rev Med Chem 1,
163-174.
Carlier PR, Du DM, Han Y, Liu J, Pang YP (1999)
Potent, easily synthesized huperzine A-tacrine hybrid
acetylcholinesterase inhibitors. Bioorg Med Chem Lett 9,
2335-2338.
Ronco C, Sorin G, Nachon F, Foucault R, Jean L,
Romieu A, Renard PY (2009) Synthesis and structureactivity relationship of Huprine derivatives as human
acetylcholinesterase inhibitors. Bioorg Med Chem 17,
4523-4536.
Ronco C, Foucault R, Gillon E, Bohn P, Nachon F,
Jean L, Renard PY (2011) New huprine derivatives
[273]
[274]
[275]
[276]
[277]
[278]
[279]
[280]
[281]
[282]
[283]
[284]
functionalized at position 9 as highly potent acetylcholinesterase inhibitors. ChemMedChem 6, 876-888.
Ronco C, Carletti E, Colletier JP, Weik M, Nachon F,
Jean L, Renard PY (2012) Huprine derivatives as subnanomolar human acetylcholinesterase inhibitors: From
rational design to validation by X-ray crystallography.
ChemMedChem 7, 400-405.
Alcala MM, Vivas NM, Hospital S, Camps P, MunozTorrero D, Badia A (2003) Characterisation of the
anticholinesterase activity of two new tacrine-huperzine
A hybrids. Neuropharmacology 44, 749-755.
Roman S, Vivas NM, Badia A, Clos MV (2002) Interaction
of a new potent anticholinesterasic compound (+/-)huprine
X with muscarinic receptors in rat brain. Neurosci Lett 325,
103-106.
Dvir H, Wong DM, Harel M, Barril X, Orozco M, Luque
FJ, Munoz-Torrero D, Camps P, Rosenberry TL, Silman
I, Sussman JL (2002) 3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1
A resolution: Kinetic and molecular dynamic correlates.
Biochemistry 41, 2970-2981.
Ratia M, Gimenez-Llort L, Camps P, Munoz-Torrero D,
Clos MV, Badia A (2010) Behavioural effects and regulation of PKCalpha and MAPK by huprine X in middle aged
mice. Pharmacol Biochem Behav 95, 485-493.
Hedberg MM, Clos MV, Ratia M, Gonzalez D, Lithner CU,
Camps P, Munoz-Torrero D, Badia A, Gimenez-Llort L,
Nordberg A (2010) Effect of huprine X on beta-amyloid,
synaptophysin and alpha7 neuronal nicotinic acetylcholine
receptors in the brain of 3xTg-AD and APPswe transgenic
mice. Neurodegener Dis 7, 379-388.
Gemma S, Gabellieri E, Huleatt P, Fattorusso C, Borriello
M, Catalanotti B, Butini S, De AM, Novellino E, Nacci V,
Belinskaya T, Saxena A, Campiani G (2006) Discovery of
huperzine A-tacrine hybrids as potent inhibitors of human
cholinesterases targeting their midgorge recognition sites.
J Med Chem 49, 3421-3425.
Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia
A, Clos MV, Relat J, Ratia M, Bartolini M, Mancini F,
Andrisano V, Salmona M, Minguillon C, Gonzalez-Munoz
GC, Rodriguez-Franco MI, Bidon-Chanal A, Luque FJ,
Munoz-Torrero D (2012) Huprine-tacrine heterodimers
as anti-amyloidogenic compounds of potential interest
against Alzheimer’s and prion diseases. J Med Chem 55,
661-669.
Munoz-Torrero D, Pera M, Relat J, Ratia M, Galdeano C,
Viayna E, Sola I, Formosa X, Camps P, Badia A, Clos
MV (2012) Expanding the multipotent profile of huprinetacrine heterodimers as disease-modifying anti-Alzheimer
agents. Neurodegener Dis 10, 96-99.
Carlier PR, Du DM, Han YF, Liu J, Perola E, Williams
ID, Pang YP (2000) Dimerization of an inactive fragment
of huperzine a produces a drug with twice the potency of
the natural product. Angew Chem Int Ed Engl 39, 17751777.
Cui W, Cui GZ, Li W, Zhang Z, Hu S, Mak S, Zhang
H, Carlier PR, Choi CL, Wong YT, Lee SM, Han Y
(2011) Bis(12)-hupyridone, a novel multifunctional dimer,
promotes neuronal differentiation more potently than its
monomeric natural analog huperzine A possibly through
alpha7 nAChR. Brain Res 1401, 10-17.
Lewis WG, Green LG, Grynszpan F, Radic Z, Carlier PR,
Taylor P, Finn MG, Sharpless KB (2002) Click chemistry
in situ: acetylcholinesterase as a reaction vessel for the
selective assembly of a femtomolar inhibitor from an array
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[285]
[286]
[287]
[288]
[289]
[290]
[291]
[292]
[293]
[294]
[295]
[296]
[297]
of building blocks. Angew Chem Int Ed Engl 41, 10531057.
Szymanski P, Janik A, Zurek E, Mikiciuk-Olasik E
(2011) Design, synthesis and biological evaluation of new
2-benzoxazolinone derivatives as potential cholinesterase
inhibitors for therapy of Alzheimer’s disease. Pharmazie
66, 399-403.
Wu ZP, Wu XW, Shen T, Li YP, Cheng X, Gu LQ, Huang
ZS, An LK (2012) Synthesis and acetylcholinesterase
and butyrylcholinesterase inhibitory activities of 7-alkoxyl
substituted indolizinoquinoline-5,12-dione derivatives.
Arch Pharm (Weinheim) 345, 175-184.
Ignasik M, Bajda M, Guzior N, Prinz M, Holzgrabe
U, Malawska B (2012) Design, synthesis and evaluation
of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives
as dual-binding site acetylcholinesterase inhibitors. Arch
Pharm (Weinheim) 345, 509-516.
Anand P, Singh B (2012) Synthesis and evaluation of novel
4-[(3H,3aH,6aH)-3-phenyl)-4,6-dioxo-2-phenyldihydro2H-pyrrolo[3,4-d]isoxazol-5(3H,6H,6aH)-yl]benzoic
acid derivatives as potent acetylcholinesterase inhibitors
and anti-amnestic agents. Bioorg Med Chem 20, 521-530.
Ashraf AM, Ismail R, Choon TS, Kumar RS, Osman
H, Arumugam N, Almansour AI, Elumalai K, Singh A
(2012) AChE inhibitor: A regio- and stereo-selective
1,3-dipolar cycloaddition for the synthesis of novel
substituted 5,6-dimethoxy spiro[5.3 ]-oxindole-spiro[6.3 ]-2,3-dihydro-1H-inden-1 -one-7-(substituted
aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole 1. Bioorg
Med Chem Lett 22, 508-511.
Li Z, Wang B, Hou JQ, Huang SL, Ou TM, Tan
JH, An LK, Li D, Gu LQ, Huang ZS (2012) 2-(2indolyl-)-4(3H)-quinazolines derivates as new inhibitors
of AChE: Design, synthesis, biological evaluation and
molecular modelling. J Enzyme Inhib Med Chem, doi:
10.3109/14756366.2012.663363 [Epubl ahead of print].
Piplani P, Rani A, Saihgal R, Sharma M (2011) Synthesis and pharmacological evaluation of some quinoline
derivatives as potential cognition enhancers. Arzneimittelforschung 61, 373-378.
Chen Y, Sun J, Fang L, Liu M, Peng S, Liao H, Lehmann
J, Zhang Y (2012) Tacrine-ferulic acid-nitric oxide (NO)
donor trihybrids as potent, multifunctional acetyl- and
butyrylcholinesterase inhibitors. J Med Chem 55, 43094321.
Wonga KY, Duchowicz PR, Mercader AG, Castro EA
(2012) QSAR applications during last decade on inhibitors
of acetylcholinesterase in Alzheimer’s disease. Mini Rev
Med Chem, [Epubl ahead of print].
Yan A, Wang K (2012) Quantitative structure and bioactivity relationship study on human acetylcholinesterase
inhibitors. Bioorg Med Chem Lett 22, 3336-3342.
Chen Y, Fang L, Peng S, Liao H, Lehmann J, Zhang Y
(2012) Discovery of a novel acetylcholinesterase inhibitor
by structure-based virtual screening techniques. Bioorg
Med Chem Lett 22, 3181-3187.
Wang K, Hu X, Wang Z, Yan A (2012) Classification of
acetylcholinesterase inhibitors and decoys by a support
vector machine. Comb Chem High Throughput Screen 15,
492-502.
Berg L, Andersson CD, Artursson E, Hornberg A, Tunemalm AK, Linusson A, Ekstrom F (2011) Targeting
acetylcholinesterase: Identification of chemical leads by
high throughput screening, structure determination and
molecular modeling. PLoS One 6, e26039.
[298]
[299]
[300]
[301]
[302]
[303]
[304]
[305]
[306]
[307]
[308]
[309]
[310]
[311]
[312]
[313]
605
Kojima J, Nakajima K, Ochiai M, Nakayama K (1997)
Effects of NIK-247 on cholinesterase and scopolamineinduced amnesia. Methods Find Exp Clin Pharmacol 19,
245-251.
Kojima J, Onodera K (1998) Effects of NIK-247 and
tacrine on muscarinic receptor subtypes in rats. Gen Pharmacol 30, 537-541.
Kojima J, Onodera K (1998) NIK-247 induces long-term
potentiation of synaptic transmission in the CA1 region of
rat hippocampal slices through M2 muscarinic receptors.
Gen Pharmacol 31, 297-300.
Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli
A, Bartolini M, Andrisano V, Valenti P, Recanatini M
(2003) 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7dimethoxy-2H-2-chromenone (AP2238) inhibits both
acetylcholinesterase and acetylcholinesterase-induced
beta-amyloid aggregation: A dual function lead for
Alzheimer’s disease therapy. J Med Chem 46, 2279-2282.
Piazzi L, Cavalli A, Belluti F, Bisi A, Gobbi S,
Rizzo S, Bartolini M, Andrisano V, Recanatini M,
Rampa A (2007) Extensive SAR and computational
studies of 3-{4-[(benzylmethylamino)methyl]phenyl}6,7-dimethoxy-2H-2-chromenone (AP2238) derivatives. J
Med Chem 50, 4250-4254.
Rizzo S, Bartolini M, Ceccarini L, Piazzi L, Gobbi S,
Cavalli A, Recanatini M, Andrisano V, Rampa A (2010)
Targeting Alzheimer’s disease: Novel indanone hybrids
bearing a pharmacophoric fragment of AP2238. Bioorg
Med Chem 18, 1749-1760.
Bayes M, Rabasseda X, Prous JR (2003) Gateways to clinical trials. Methods Find Exp Clin Pharmacol 25, 565-597.
Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca
U, Thal LJ (1999) Efficacy and safety of eptastigmine for
the treatment of patients with Alzheimer’s disease. Neurology 52, 700-708.
Imbimbo BP, Troetel WM, Martelli P, Lucchelli F
(2000) A 6-month, double-blind, placebo-controlled trial
of eptastigmine in Alzheimer’s disease. Dement Geriatr
Cogn Disord 11, 17-24.
Braida D, Ottonello F, Sala M (2000) Eptastigmine
improves eight-arm radial maze performance in aged rats.
Pharmacol Res 42, 299-304.
Braida D, Ottonello F, Sala M (2000) Eptastigmine restores
the aged rat’s normal cortical spectral power pattern. Pharmacol Res 42, 495-500.
Braida D, Sala M (2001) Eptastigmine: Ten years of
pharmacology, toxicology, pharmacokinetic, and clinical
studies. CNS Drug Rev 7, 369-386.
Trabace L, Cassano T, Loverre A, Steardo L, Cuomo
V (2002) CHF2819: Pharmacological profile of a novel
acetylcholinesterase inhibitor. CNS Drug Rev 8, 53-69.
Trabace L, Cassano T, Colaianna M, Castrignano S,
Giustino A, Amoroso S, Steardo L, Cuomo V (2007) Neurochemical and neurobehavioral effects of ganstigmine
(CHF2819), a novel acetylcholinesterase inhibitor, in rat
prefrontal cortex: An in vivo study. Pharmacol Res 56,
288-294.
Jhee SS, Fabbri L, Piccinno A, Monici P, Moran S, Zarotsky V, Tan EY, Frackiewicz EJ, Shiovitz T (2003) First
clinical evaluation of ganstigmine in patients with probable
Alzheimer’s disease. Clin Neuropharmacol 26, 164169.
Mazzucchelli M, Porrello E, Villetti G, Pietra C, Govoni
S, Racchi M (2003) Characterization of the effect of
ganstigmine (CHF2819) on amyloid precursor protein
606
[314]
[315]
[316]
[317]
[318]
[319]
[320]
[321]
[322]
[323]
[324]
[325]
[326]
[327]
[328]
[329]
[330]
[331]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
metabolism in SH-SY5Y neuroblastoma cells. J Neural
Transm 110, 935-947.
Windisch M, Hutter-Paier B, Jerkovic L, Imbimbo B,
Villetti G (2003) The protective effect of ganstigmine
against amyloid beta 25-35 neurotoxicity on chicken
cortical neurons is independent from the cholinesterase
inhibition. Neurosci Lett 341, 181-184.
Bartolucci C, Siotto M, Ghidini E, Amari G, Bolzoni
PT, Racchi M, Villetti G, Delcanale M, Lamba D (2006)
Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active
carbamate based anti-alzheimer drug ganstigmine (CHF2819). J Med Chem 49, 5051-5058.
Hock FJ, Gerhards HJ, Wiemer G, Stechl J, Ruger W,
Urbach H (1989) Effects of the novel compound, Hoe
065, upon impaired learning and memory in rodents. Eur
J Pharmacol 171, 79-85.
Wiemer G, Becker R, Gerhards H, Hock F, Stechl J, Ruger
W (1989) Effects of Hoe 065, a compound structurally
related to inhibitors of angiotensin converting enzyme, on
acetylcholine metabolism in rat brain. Eur J Pharmacol
166, 31-39.
Grupp LA, Chow SY (1991) Effects of the novel compound Hoe 065, a central enhancer of cholinergic activity,
on voluntary alcohol consumption in rats. Brain Res Bull
26, 617-619.
Liston DR, Nielsen JA, Villalobos A, Chapin D, Jones SB,
Hubbard ST, Shalaby IA, Ramirez A, Nason D, White WF
(2004) Pharmacology of selective acetylcholinesterase
inhibitors: Implications for use in Alzheimer’s disease. Eur
J Pharmacol 486, 9-17.
Giacobini E (1997) Metrifonate. A viewpoint. Drugs
Aging 11, 497.
Schneider LS, Giacobini E (1999) Metrifonate: A
cholinesterase inhbitor for Alzheimer’s disease therapy.
CNS Drug Rev 5, 13-26.
Schneider LS (2000) Metrifonate for Alzheimer’s disease
patients. J Clin Psychiatry 61, 218-219.
Farlow MR, Cyrus PA (2000) Metrifonate therapy in
Alzheimer’s disease: A pooled analysis of four randomized, double-blind, placebo-controlled trials. Dement
Geriatr Cogn Disord 11, 202-211.
Ormrod D, Spencer C (2000) Metrifonate. A review of its
use in Alzheimer’s disease. CNS Drugs 13, 443-467.
Giacobini E (2004) Cholinesterase inhibitors: New roles
and therapeutic alternatives. Pharmacol Res 50, 433-440.
Thatte U (2005) Phenserine Axonyx. Curr Opin Investig
Drugs 6, 729-739.
Klein J (2007) Phenserine. Expert Opin Investig Drugs 16,
1087-1097.
Kadir A, Andreasen N, Almkvist O, Wall A, Forsberg A,
Engler H, Hagman G, Larksater M, Winblad B, Zetterberg
H, Blennow K, Langstrom B, Nordberg A (2008) Effect
of phenserine treatment on brain functional activity and
amyloid in Alzheimer’s disease. Ann Neurol 63, 621-631.
Winblad B, Giacobini E, Frolich L, Friedhoff LT, Bruinsma
G, Becker RE, Greig NH (2010) Phenserine efficacy in
Alzheimer’s disease. J Alzheimers Dis 22, 1201-1208.
Benech H, Vincenti M, Fouchart F, Pruvost A, Vienet R,
Istin M, Grognet JM (1998) Development and in vivo
assessment of a transdermal system for physostigmine.
Methods Find Exp Clin Pharmacol 20, 489-498.
Moller H-J, Hampel H, Hegerl U, Schmitt W, Walter
K (1999) Double-blind, randomized, placebo-controlled
clinical trial on the efficacy and tolerability of a physostig-
[332]
[333]
[334]
[335]
[336]
[337]
[338]
[339]
[340]
[341]
[342]
[343]
[344]
[345]
[346]
[347]
mine patch in patients with senile dementia of the
Alzheimer type. Pharmacopsychiatry 32, 99-106.
Kim JH, Lee CH, Choi HK (2002) Transdermal delivery
of physostigmine: Effects of enhancers and pressuresensitive adhesives. Drug Dev Ind Pharm 28, 833-839.
Cerasoli DM, Griffiths EM, Doctor BP, Saxena A, Fedorko
JM, Greig NH, Yu QS, Huang Y, Wilgus H, Karatzas CN,
Koplovitz I, Lenz DE (2005) In vitro and in vivo characterization of recombinant human butyrylcholinesterase
(Protexia) as a potential nerve agent bioscavenger. Chem
Biol Interact 157-158 363-365.
Mumford H, Troyer JK (2011) Post-exposure therapy with
recombinant human BuChE following percutaneous VX
challenge in guinea-pigs. Toxicol Lett 206, 29-34.
Natori K, Okazaki Y, Irie T, Katsube J (1990) Pharmacological and biochemical assessment of SM-10888, a novel
cholinesterase inhibitor. Jpn J Pharmacol 53, 145-155.
Okazaki Y, Natori K, Irie T, Katsube J (1990) Effect of a
novel CNS-selective cholinesterase inhibitor, SM-10888,
on habituation and passive avoidance responses in mice.
Jpn J Pharmacol 53, 211-220.
Xu M, Nakamura Y, Yamamoto T, Natori K, Irie T, Utsumi
H, Kato T (1991) Determination of basal acetylcholine
release in vivo by rat brain dialysis with a U-shaped cannula: Effect of SM-10888, a putative therapeutic drug for
Alzheimer’s disease. Neurosci Lett 123, 179-182.
Schroeder H, Dumont I, Boyet S, Mocaer E, Nehlig
A (1992) Effects of the acute administration of a new
trimethylxanthine derivative, S 9977-2, on local cerebral
blood flow and glucose utilization in the rat. Eur J Pharmacol 220, 217-229.
Trudeau LE, Fossier P, Baux G, Tauc L (1992) Xanthine
derivatives IBMX and S-9977-2 potentiate transmission
at an Aplysia central cholinergic synapse. Brain Res 586,
78-85.
Boulanger CM, Hughes H, Bond RA, Rafla E, Vanhoutte
PM (1993) Effects of S9977 on adrenergic neurotransmission. Gen Pharmacol 24, 429-434.
Fernandez-Novoa L, Alvarez XA, tolle-Sarbach S, Guez
D, Zas R, Polo E, Cacabelos R (1996) Effects of S-9977-2
on histamine levels in rats. Methods Find Exp Clin Pharmacol 18, 197-203.
Braga MF, Harvey AL, Rowan EG (1991) Effects of
tacrine, velnacrine (HP029), suronacrine (HP128), and
3,4-diaminopyridine on skeletal neuromuscular transmission in vitro. Br J Pharmacol 102, 909-915.
Huff FJ, Antuono P, Murphy M, Beyer J, Dobson C (1991)
Potential clinical use of an adrenergic/cholinergic agent
(HP 128) in the treatment of Alzheimer’s disease. Ann N Y
Acad Sci 640, 263-267.
Isoma K, Ishikawa M, Ohta M, Ogawa Y, Hasegawa H,
Kohda T, Kamei J (2002) Effects of T-82, a new quinoline derivative, on cholinesterase activity and extracellular
acetylcholine concentration in rat brain. Jpn J Pharmacol
88, 206-212.
Isomae K, Morimoto S, Hasegawa H, Morita K, Kamei
J (2003) Effects of T-82, a novel acetylcholinesterase
inhibitor, on impaired learning and memory in passive
avoidance task in rats. Eur J Pharmacol 465, 97-103.
Yu Q, Holloway HW, Utsuki T, Brossi A, Greig NH (1999)
Synthesis of novel phenserine-based-selective inhibitors
of butyrylcholinesterase for Alzheimer’s disease. J Med
Chem 42, 1855-1861.
Yu QS, Holloway HW, Luo W, Lahiri DK, Brossi A,
Greig NH (2010) Long-acting anticholinesterases for
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[348]
[349]
[350]
[351]
[352]
[353]
[354]
[355]
[356]
[357]
[358]
[359]
[360]
[361]
[362]
myasthenia gravis: Synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine
and physostigmine. Bioorg Med Chem 18, 4687-4693.
Kamal MA, Greig NH, Alhomida AS, Al-Jafari AA (2000)
Kinetics of human acetylcholinesterase inhibition by the
novel experimental Alzheimer therapeutic agent, tolserine.
Biochem Pharmacol 60, 561-570.
Hartmann J, Kiewert C, Duysen EG, Lockridge O, Greig
NH, Klein J (2007) Excessive hippocampal acetylcholine
levels in acetylcholinesterase-deficient mice are moderated by butyrylcholinesterase activity. J Neurochem 100,
1421-1429.
Zemlan FP (1996) Velnacrine for the treatment of
Alzheimer’s disease: A double-blind, placebo-controlled
trial. The mentane study group. J Neural Transm 103,
1105-1116.
Zemlan FP, Keys M, Richter RW, Strub RL (1996)
Double-blind placebo-controlled study of velnacrine in
Alzheimer’s disease. Life Sci 58, 1823-1832.
Hatip-Al-Khatib I, Takashi A, Egashira N, Iwasaki K,
Fujiwara M (2004) Comparison of the effect of TAK-147
(zanapezil) and E-2020 (donepezil) on extracellular acetylcholine level and blood flow in the ventral hippocampus
of freely moving rats. Brain Res 1012, 169-176.
Hatip-Al-Khatib I, Iwasaki K, Yoshimitsu Y, Arai T,
Egashira N, Mishima K, Ikeda T, Fujiwara M (2005) Effect
of oral administration of zanapezil (TAK-147) for 21 days
on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats. Br J Pharmacol 145,
1035-1044.
Hornsperger JM, Collard JN, Heydt JG, Giacobini E,
Funes S, Dow J, Schirlin D (1994) Trimethylsilylated trifluoromethyl ketones, a novel class of acetylcholinesterase
inhibitors: Biochemical and pharmacological profile of
MDL 73,745. Biochem Soc Trans 22, 758-763.
Cutler NR, Seifert RD, Schleman MM, Sramek JJ, Szylleyko OJ, Howard DR, Barchowsky A, Wardle TS, Brass
EP (1995) Acetylcholinesterase inhibition by zifrosilone:
Pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 58, 54-61.
Zhu XD, Giacobini E, Hornsperger JM (1995) Effect of
MDL 73,745 on acetylcholine and biogenic amine levels
in rat cortex. Eur J Pharmacol 276, 93-99.
Youdim MB, Buccafusco JJ (2005) Multi-functional drugs
for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26, 27-35.
del Monte-Millan M, Garcia-Palomero E, Valenzuela R,
Usan P, de AC, Munoz-Ruiz P, Rubio L, Dorronsoro I,
Martinez A, Medina M (2006) Dual binding site acetylcholinesterase inhibitors: Potential new disease-modifying
agents for AD. J Mol Neurosci 30, 85-88.
Martinez A, Castro A (2006) Novel cholinesterase
inhibitors as future effective drugs for the treatment of
Alzheimer’s disease. Expert Opin Investig Drugs 15,
1-12.
Munoz-Torrero D, Camps P (2006) Dimeric and hybrid
anti-Alzheimer drug candidates. Curr Med Chem 13, 399422.
Munoz-Torrero D (2008) Acetylcholinesterase inhibitors
as disease-modifying therapies for Alzheimer’s disease.
Curr Med Chem 15, 2433-2455.
Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti
V, Recanatini M, Melchiorre C (2008) Multi-targetdirected ligands to combat neurodegenerative diseases. J
Med Chem 51, 347-372.
[363]
[364]
[365]
[366]
[367]
[368]
[369]
[370]
[371]
[372]
[373]
[374]
[375]
[376]
[377]
[378]
607
Bolognesi ML, Matera R, Minarini A, Rosini M, Melchiorre C (2009) Alzheimer’s disease: New approaches to
drug discovery. Curr Opin Chem Biol 13, 303-308.
Bolognesi ML, Simoni E, Rosini M, Minarini A, Tumiatti V, Melchiorre C (2011) Multitarget-directed ligands:
Innovative chemical probes and therapeutic tools against
Alzheimer’s disease. Curr Top Med Chem 11, 27972806.
Buccafusco JJ (2009) Multifunctional receptor-directed
drugs for disorders of the central nervous system. Neurotherapeutics 6, 4-13.
Melchiorre C, Bolognesi ML, Minarini A, Rosini M, Tumiatti V (2010) Polyamines in drug discovery: From the
universal template approach to the multitarget-directed ligand design strategy. J Med Chem 53, 5906-5914.
Leon R, Garcia AG, Marco-Contelles J (2011) Recent
advances in the multitarget-directed ligands approach for
the treatment of Alzheimer’s disease. Med Res Rev, doi:
10.1002/med.20248 [Epubl ahead of print].
Marco-Contelles J, Soriano E (2011) The medicinal chemistry of hybrid-based drugs targeting multiple sites of
action. Curr Top Med Chem 11, 2714-2715.
Bajda M, Guzior N, Ignasik M, Malawska B (2011) Multitarget-directed ligands in Alzheimer’s disease treatment.
Curr Med Chem 18, 4949-4975.
Rampa A, Belluti F, Gobbi S, Bisi A (2011) Hybrid-based
multi-target ligands for the treatment of Alzheimer’s disease. Curr Top Med Chem 11, 2716-2730.
Melchiorre C, Andrisano V, Bolognesi ML, Budriesi R,
Cavalli A, Cavrini V, Rosini M, Tumiatti V, Recanatini M (1998) Acetylcholinesterase noncovalent inhibitors
based on a polyamine backbone for potential use against
Alzheimer’s disease. J Med Chem 41, 4186-4189.
Starks KM, Ortega-Vilain AC, Buccafusco JJ, Powers
JC (1996) Novel pyridinium derivatives as inhibitors for
acetylcholinesterase. J Enzyme Inhib 10, 27-45.
Buccafusco JJ, Powers JC, Hernandez MA, Prendergast
MA, Terry AV, Jonnala RR (2007) MHP-133, a drug with
multiple CNS targets: Potential for neuroprotection and
enhanced cognition. Neurochem Res 32, 1224-1237.
Borroni E, Damsma G, Giovacchini C, Mutel V, JakobRotne R, Da PM (1994) A novel acetylcholinesterase
inhibitor, Ro 46-5934, which interacts with muscarinic M2
receptors. Biochem Soc Trans 22, 755-758.
Fang L, Jumpertz S, Zhang Y, Appenroth D, Fleck C,
Mohr K, Trankle C, Decker M (2010) Hybrid molecules
from xanomeline and tacrine: Enhanced tacrine actions on
cholinesterases and muscarinic M1 receptors. J Med Chem
53, 2094-2103.
Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente
M, Linker C, Casanueva OI, Soto C, Garrido J (1996)
Acetylcholinesterase accelerates assembly of amyloidbeta-peptides into Alzheimer’s fibrils: Possible role of the
peripheral site of the enzyme. Neuron 16, 881-891.
Alvarez A, Opazo C, Alarcon R, Garrido J, Inestrosa NC
(1997) Acetylcholinesterase promotes the aggregation of
amyloid-beta-peptide fragments by forming a complex
with the growing fibrils. J Mol Biol 272, 348-361.
Alvarez A, Alarcon R, Opazo C, Campos EO, Munoz
FJ, Calderon FH, Dajas F, Gentry MK, Doctor BP, De
Mello FG, Inestrosa NC (1998) Stable complexes involving acetylcholinesterase and amyloid-beta peptide change
the biochemical properties of the enzyme and increase
the neurotoxicity of Alzheimer’s fibrils. J Neurosci 18,
3213-3223.
608
[379]
[380]
[381]
[382]
[383]
[384]
[385]
[386]
[387]
[388]
[389]
[390]
[391]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman
I, Inestrosa NC (2001) A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril
formation. Biochemistry 40, 10447-10457.
Bartolini M, Bertucci C, Cavrini V, Andrisano V (2003)
beta-Amyloid aggregation induced by human acetylcholinesterase: Inhibition studies. Biochem Pharmacol 65,
407-416.
Munoz-Ruiz P, Rubio L, Garcia-Palomero E, Dorronsoro
I, del Monte-Millan M, Valenzuela R, Usan P, de AC, Bartolini M, Andrisano V, Bidon-Chanal A, Orozco M, Luque
FJ, Medina M, Martinez A (2005) Design, synthesis,
and biological evaluation of dual binding site acetylcholinesterase inhibitors: New disease-modifying agents
for Alzheimer’s disease. J Med Chem 48, 7223-7233.
Castro A, Martinez A (2001) Peripheral and dual binding site acetylcholinesterase inhibitors: Implications in
treatment of Alzheimer’s disease. Mini Rev Med Chem 1,
267-272.
Belluti F, Rampa A, Piazzi L, Bisi A, Gobbi S, Bartolini
M, Andrisano V, Cavalli A, Recanatini M, Valenti P (2005)
Cholinesterase inhibitors: Xanthostigmine derivatives
blocking the acetylcholinesterase-induced beta-amyloid
aggregation. J Med Chem 48, 4444-4456.
Camps P, Formosa X, Munoz-Torrero D, Petrignet J, Badia
A, Clos MV (2005) Synthesis and pharmacological evaluation of huprine-tacrine heterodimers: Subnanomolar dual
binding site acetylcholinesterase inhibitors. J Med Chem
48, 1701-1704.
del Monte-Millan M, Garcia-Palomero E, Valenzuela R,
Usan P, de AC, Munoz-Ruiz P, Rubio L, Dorronsoro I,
Martinez A, Medina M (2006) Dual binding site acetylcholinesterase inhibitors: Potential new disease-modifying
agents for AD. J Mol Neurosci 30, 85-88.
Garcia-Palomero E, Munoz P, Usan P, Garcia P, Delgado
E, De AC, Valenzuela R, Rubio L, Medina M, Martinez
A (2008) Potent beta-amyloid modulators. Neurodegener
Dis 5, 153-156.
Carvajal FJ, Inestrosa NC (2011) Interactions of AChE
with Abeta aggregates in Alzheimer’s brain: Therapeutic
relevance of IDN 5706. Front Mol Neurosci 4, 19.
Fernandez-Bachiller MI, Perez C, Gonzalez-Munoz GC,
Conde S, Lopez MG, Villarroya M, Garcia AG, RodriguezFranco MI (2010) Novel tacrine-8-hydroxyquinoline
hybrids as multifunctional agents for the treatment of
Alzheimer’s disease, with neuroprotective, cholinergic,
antioxidant, and copper-complexing properties. J Med
Chem 53, 4927-4937.
Antequera D, Bolos M, Spuch C, Pascual C, Ferrer I,
Fernandez-Bachiller MI, Rodriguez-Franco MI, Carro E
(2012) Effects of a tacrine-8-hydroxyquinoline hybrid
(IQM-622) on Abeta accumulation and cell death: Involvement in hippocampal neuronal loss in Alzheimer’s disease.
Neurobiol Dis 46, 682-691.
Kapkova P, Alptuzun V, Frey P, Erciyas E, Holzgrabe U
(2006) Search for dual function inhibitors for Alzheimer’s
disease: Synthesis and biological activity of acetylcholinesterase inhibitors of pyridinium-type and their
Abeta fibril formation inhibition capacity. Bioorg Med
Chem 14, 472-478.
Kwon YE, Park JY, No KT, Shin JH, Lee SK, Eun JS,
Yang JH, Shin TY, Kim DK, Chae BS, Leem JY, Kim
KH (2007) Synthesis, in vitro assay, and molecular modeling of new piperidine derivatives having dual inhibitory
potency against acetylcholinesterase and Abeta1-42 aggre-
[392]
[393]
[394]
[395]
[396]
[397]
[398]
[399]
[400]
[401]
gation for Alzheimer’s disease therapeutics. Bioorg Med
Chem 15, 6596-6607.
Camps P, Formosa X, Galdeano C, Gomez T, MunozTorrero D, Scarpellini M, Viayna E, Badia A, Clos MV,
Camins A, Pallas M, Bartolini M, Mancini F, Andrisano
V, Estelrich J, Lizondo M, Bidon-Chanal A, Luque FJ
(2008) Novel donepezil-based inhibitors of acetyl- and
butyrylcholinesterase and acetylcholinesterase-induced
beta-amyloid aggregation. J Med Chem 51, 3588-3598.
Camps P, Formosa X, Galdeano C, Munoz-Torrero D,
Ramirez L, Gomez E, Isambert N, Lavilla R, Badia A,
Clos MV, Bartolini M, Mancini F, Andrisano V, Arce
MP, Rodriguez-Franco MI, Huertas O, Dafni T, Luque FJ
(2009) Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as
a novel family of acetylcholinesterase- and beta-amyloiddirected anti-Alzheimer compounds. J Med Chem 52,
5365-5379.
Alptuzun V, Prinz M, Horr V, Scheiber J, Radacki
K, Fallarero A, Vuorela P, Engels B, Braunschweig
H, Erciyas E, Holzgrabe U (2010) Interaction of
(benzylidene-hydrazono)-1,4-dihydropyridines with betaamyloid, acetylcholine, and butyrylcholine esterases.
Bioorg Med Chem 18, 2049-2059.
Bolognesi ML, Bartolini M, Mancini F, Chiriano G, Ceccarini L, Rosini M, Milelli A, Tumiatti V, Andrisano
V, Melchiorre C (2010) Bis(7)-tacrine derivatives as
multitarget-directed ligands: Focus on anticholinesterase
and antiamyloid activities. ChemMedChem 5, 12151220.
Viayna E, Gomez T, Galdeano C, Ramirez L, Ratia M,
Badia A, Clos MV, Verdaguer E, Junyent F, Camins A,
Pallas M, Bartolini M, Mancini F, Andrisano V, Arce MP,
Rodriguez-Franco MI, Bidon-Chanal A, Luque FJ, Camps
P, Munoz-Torrero D (2010) Novel huprine derivatives with
inhibitory activity toward beta-amyloid aggregation and
formation as disease-modifying anti-Alzheimer drug candidates. ChemMedChem 5, 1855-1870.
Mohamed T, Zhao X, Habib LK, Yang J, Rao PP
(2011) Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine
derivatives: Dual activity as cholinesterase and Abetaaggregation inhibitors. Bioorg Med Chem 19, 2269-2281.
Mohamed T, Yeung JC, Rao PP (2011) Development of 2-substituted-N-(naphth-1-ylmethyl) and Nbenzhydrylpyrimidin-4-amines as dual cholinesterase and
Abeta-aggregation inhibitors: Synthesis and biological
evaluation. Bioorg Med Chem Lett 21, 5881-5887.
Shi A, Huang L, Lu C, He F, Li X (2011) Synthesis, biological evaluation and molecular modeling of
novel triazole-containing berberine derivatives as acetylcholinesterase and beta-amyloid aggregation inhibitors.
Bioorg Med Chem 19, 2298-2305.
Galdeano C, Viayna E, Sola I, Formosa X, Camps P, Badia
A, Clos MV, Relat. J, Ratia M, Bartolini M, Mancini F,
Andrisano V, Salmona M, Minguillon C, Gonzalez-Munoz
GC, Rodriguez-Franco MI, Bidon-Chanal A, Luque FJ,
Munoz-Torrero D (2012) Huprine-tacrine heterodimers
as anti-amyloidogenic compounds of potential interest
against Alzheimer’s and prion diseases. J Med Chem 55,
661-669.
Munoz-Torrero D, Pera M, Relat J, Ratia M, Galdeano C,
Viayna E, Sola I, Formosa X, Camps P, Badia A, Clos
MV (2012) Expanding the multipotent profile of huprinetacrine heterodimers as disease-modifying anti-Alzheimer
agents. Neurodegener Dis 10, 96-99.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[402]
[403]
[404]
[405]
[406]
[407]
[408]
[409]
[410]
[411]
[412]
[413]
[414]
[415]
Yan JW, Li YP, Ye WJ, Chen SB, Hou JQ, Tan JH, Ou TM,
Li D, Gu LQ, Huang ZS (2012) Design, synthesis and evaluation of isaindigotone derivatives as dual inhibitors for
acetylcholinesterase and amyloid beta aggregation. Bioorg
Med Chem 20, 2527-2534.
Tang H, Zhao HT, Zhong SM, Wang ZY, Chen ZF, Liang H
(2012) Novel oxoisoaporphine-based inhibitors of acetyland butyrylcholinesterase and acetylcholinesteraseinduced beta-amyloid aggregation. Bioorg Med Chem
Lett 22, 2257-2261.
Shan WJ, Huang L, Zhou Q, Meng FC, Li XS (2011)
Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant,
inhibitors of acetylcholinesterase, butyrylcholinesterase
and amyloid-beta aggregation. Eur J Med Chem 46, 58855893.
Rosini M, Andrisano V, Bartolini M, Bolognesi ML, Hrelia
P, Minarini A, Tarozzi A, Melchiorre C (2005) Rational
approach to discover multipotent anti-Alzheimer drugs.
J Med Chem 48, 360-363.
Packer L (1998) alpha-Lipoic acid: A metabolic antioxidant which regulates NF-kappa B signal transduction and
protects against oxidative injury. Drug Metab Rev 30, 245275.
Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young
S, Hager K, Engel J, Munch G (2007) Lipoic acid as a novel
treatment for Alzheimer’s disease and related dementias.
Pharmacol Ther 113, 154-164.
Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Munch G (2008) Lipoic acid
as an anti-inflammatory and neuroprotective treatment for
Alzheimer’s disease. Adv Drug Deliv Rev 60, 1463-1470.
Zhang L, Xing GQ, Barker JL, Chang Y, Maric D, Ma W,
Li BS, Rubinow DR (2001) Alpha-lipoic acid protects rat
cortical neurons against cell death induced by amyloid and
hydrogen peroxide through the Akt signalling pathway.
Neurosci Lett 312, 125-128.
Cavalli A, Bolognesi ML, Capsoni S, Andrisano V,
Bartolini M, Margotti E, Cattaneo A, Recanatini M,
Melchiorre C (2007) A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew Chem Int
Ed Engl 46, 3689-3692.
Bolognesi ML, Cavalli A, Melchiorre C (2009) Memoquin: A multi-target-directed ligand as an innovative
therapeutic opportunity for Alzheimer’s disease. Neurotherapeutics 6, 152-162.
Bolognesi ML, Cavalli A, Melchiorre C (2009) Memoquin: A multi-target-directed ligand as an innovative
therapeutic opportunity for Alzheimer’s disease. Neurotherapeutics 6, 152-162.
Bolognesi ML, Bartolini M, Rosini M, Andrisano V,
Melchiorre C (2009) Structure-activity relationships of
memoquin: Influence of the chain chirality in the multitarget mechanism of action. Bioorg Med Chem Lett 19,
4312-4315.
Bolognesi ML, Chiriano G, Bartolini M, Mancini F,
Bottegoni G, Maestri V, Czvitkovich S, Windisch M,
Cavalli A, Minarini A, Rosini M, Tumiatti V, Andrisano V,
Melchiorre C (2011) Synthesis of monomeric derivatives
to probe memoquin’s bivalent interactions. J Med Chem
54, 8299-8304.
Bolognesi ML, Bartolini M, Tarozzi A, Morroni F, Lizzi
F, Milelli A, Minarini A, Rosini M, Hrelia P, Andrisano V,
Melchiorre C (2011) Multitargeted drugs discovery: Balancing anti-amyloid and anticholinesterase capacity in a
[416]
[417]
[418]
[419]
[420]
[421]
[422]
[423]
[424]
[425]
[426]
609
single chemical entity. Bioorg Med Chem Lett 21, 26552658.
Rodriguez-Franco MI, Fernandez-Bachiller MI, Perez
C, Hernandez-Ledesma B, Bartolome B (2006) Novel
tacrine-melatonin hybrids as dual-acting drugs for
Alzheimer disease, with improved acetylcholinesterase
inhibitory and antioxidant properties. J Med Chem 49,
459-462.
Fernandez-Bachiller MI, Perez C, Campillo NE, Paez
JA, Gonzalez-Munoz GC, Usan P, Garcia-Palomero E,
Lopez MG, Villarroya M, Garcia AG, Martinez A,
Rodriguez-Franco MI (2009) Tacrine-melatonin hybrids
as multifunctional agents for Alzheimer’s disease, with
cholinergic, antioxidant, and neuroprotective properties.
ChemMedChem 4, 828-841.
Gonzalez-Munoz GC, Arce MP, Lopez B, Perez C,
Villarroya M, Lopez MG, Garcia AG, Conde S,
Rodriguez-Franco MI (2010) Old phenothiazine and
dibenzothiadiazepine derivatives for tomorrow’s neuroprotective therapies against neurodegenerative diseases.
Eur J Med Chem 45, 6152-6158.
Gonzalez-Munoz GC, Arce MP, Lopez B, Perez
C, Romero A, del BL, Martin-de-Saavedra MD,
Egea J, Leon R, Villarroya M, Lopez MG,
Garcia AG, Conde S, Rodriguez-Franco MI (2011)
N-acylaminophenothiazines: Neuroprotective agents
displaying multifunctional activities for a potential
treatment of Alzheimer’s disease. Eur J Med Chem 46,
2224-2235.
Fang L, Kraus B, Lehmann J, Heilmann J, Zhang Y, Decker
M (2008) Design and synthesis of tacrine-ferulic acid
hybrids as multi-potent anti-Alzheimer drug candidates.
Bioorg Med Chem Lett 18, 2905-2909.
Salga SM, Ali HM, Abdullah MA, Abdelwahab SI,
Wai LK, Buckle MJ, Sukumaran SD, Hadi AH (2011)
Synthesis, characterization, acetylcholinesterase inhibition, molecular modeling and antioxidant activities
of some novel Schiff bases derived from 1-(2ketoiminoethyl)piperazines. Molecules 16, 9316-9330.
Shan WJ, Huang L, Zhou Q, Meng FC, Li XS (2011)
Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant,
inhibitors of acetylcholinesterase, butyrylcholinesterase
and amyloid-beta aggregation. Eur J Med Chem 46, 58855893.
Piazzi L, Cavalli A, Colizzi F, Belluti F, Bartolini M,
Mancini F, Recanatini M, Andrisano V, Rampa A (2008)
Multi-target-directed coumarin derivatives: hAChE and
BACE1 inhibitors as potential anti-Alzheimer compounds.
Bioorg Med Chem Lett 18, 423-426.
Zhu Y, Xiao K, Ma L, Xiong B, Fu Y, Yu H, Wang W, Wang
X, Hu D, Peng H, Li J, Gong Q, Chai Q, Tang X, Zhang
H, Li J, Shen J (2009) Design, synthesis and biological
evaluation of novel dual inhibitors of acetylcholinesterase
and beta-secretase. Bioorg Med Chem 17, 1600-1613.
Fernandez-Bachiller MI, Perez C, Monjas L, Rademann
J, Rodriguez-Franco MI (2012) New tacrine-4-oxo-4Hchromene hybrids as multifunctional agents for the
treatment of Alzheimer’s disease, with cholinergic, antioxidant, and beta-amyloid-reducing properties. J Med Chem
55, 1303-1317.
Huang W, Tang L, Shi Y, Huang S, Xu L, Sheng R,
Wu P, Li J, Zhou N, Hu Y (2011) Searching for the
Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds
610
[427]
[428]
[429]
[430]
[431]
[432]
[433]
[434]
[435]
[436]
[437]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
with AChE, H(3)R and BACE 1 inhibitory activities.
Bioorg Med Chem 19, 7158-7167.
Vezenkov L, Sevalle J, Danalev D, Ivanov T, Bakalova
A, Georgieva M, Checler F (2012) Galantamine-based
hybrid molecules with acetylcholinesterase, butyrylcholinesterase and gamma-secretase inhibition activities.
Curr Alzheimer Res 9, 600-605.
Liu J, Ho W, Lee NT, Carlier PR, Pang Y, Han Y (2000)
Bis(7)-tacrine, a novel acetylcholinesterase inhibitor,
reverses AF64A-induced deficits in navigational memory
in rats. Neurosci Lett 282, 165-168.
Wu DC, Xiao XQ, Ng AK, Chen PM, Chung W, Lee
NT, Carlier PR, Pang YP, Yu AC, Han YF (2000) Protection against ischemic injury in primary cultured mouse
astrocytes by bis(7)-tacrine, a novel acetylcholinesterase
inhibitor [corrected]. Neurosci Lett 288, 95-98.
Xiao XQ, Lee NT, Carlier PR, Pang Y, Han YF
(2000) Bis(7)-tacrine, a promising anti-Alzheimer’s agent,
reduces hydrogen peroxide-induced injury in rat pheochromocytoma cells: Comparison with tacrine. Neurosci Lett
290, 197-200.
Li W, Pi R, Chan HH, Fu H, Lee NT, Tsang HW, Pu Y,
Chang DC, Li C, Luo J, Xiong K, Li Z, Xue H, Carlier PR, Pang Y, Tsim KW, Li M, Han Y (2005) Novel
dimeric acetylcholinesterase inhibitor bis7-tacrine, but not
donepezil, prevents glutamate-induced neuronal apoptosis
by blocking N-methyl-D-aspartate receptors. J Biol Chem
280, 18179-18188.
Fu H, Li W, Lao Y, Luo J, Lee NT, Kan KK, Tsang HW,
Tsim KW, Pang Y, Li Z, Chang DC, Li M, Han Y (2006)
Bis(7)-tacrine attenuates beta amyloid-induced neuronal
apoptosis by regulating L-type calcium channels. J Neurochem 98, 1400-1410.
Li W, Mak M, Jiang H, Wang Q, Pang Y, Chen K, Han
Y (2009) Novel anti-Alzheimer’s dimer Bis(7)-cognitin:
Cellular and molecular mechanisms of neuroprotection through multiple targets. Neurotherapeutics 6, 187201.
Orozco C, de Los RC, Arias E, Leon R, Garcia AG, Marco JL, Villarroya M, Lopez MG (2004)
ITH4012 (ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4phenylbenzol[1,8]naphthyridine-3-car boxylate), a novel
acetylcholinesterase inhibitor with “calcium promotor”
and neuroprotective properties. J Pharmacol Exp Ther
310, 987-994.
Marco-Contelles J, Leon R, de Los RC, Guglietta A,
Terencio J, Lopez MG, Garcia AG, Villarroya M (2006)
Novel multipotent tacrine-dihydropyridine hybrids with
improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of
Alzheimer’s disease. J Med Chem 49, 7607-7610.
Marco-Contelles J, Leon R, de Los RC, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ,
Rodriguez-Franco MI, Lopez B, Lopez MG, Garcia AG,
Carreiras MC, Villarroya M (2009) Tacripyrines, the first
tacrine-dihydropyridine hybrids, as multitarget-directed
ligands for the treatment of Alzheimer’s disease. J Med
Chem 52, 2724-2732.
Pereira JD, Caricati-Neto A, Miranda-Ferreira R, Smaili
SS, Godinho RO, de Los RC, Leon R, Villaroya M,
Samadi A, Marco-Contelles J, Jurkiewicz NH, Garcia
AG, Jurkiewicz A (2011) Effects of novel tacripyrines
ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity. Eur
J Pharmacol 660, 411-419.
[438]
[439]
[440]
[441]
[442]
[443]
[444]
[445]
[446]
[447]
[448]
[449]
Bartolini M, Pistolozzi M, Andrisano V, Egea J, Lopez
MG, Iriepa I, Moraleda I, Galvez E, Marco-Contelles
J, Samadi A (2011) Chemical and pharmacological
studies on enantiomerically pure p-methoxytacripyrines,
promising multi-target-directed ligands for the treatment of Alzheimer’s disease. ChemMedChem 6, 19901997.
Valero T, del BL, Egea J, Canas N, Martinez A, Garcia
AG, Villarroya M, Lopez MG (2009) NP04634 prevents
cell damage caused by calcium overload and mitochondrial
disruption in bovine chromaffin cells. Eur J Pharmacol
607, 47-53.
Degroot A, Kofalvi A, Wade MR, Davis RJ, Rodrigues RJ,
Rebola N, Cunha RA, Nomikos GG (2006) CB1 receptor
antagonism increases hippocampal acetylcholine release:
Site and mechanism of action. Mol Pharmacol 70, 12361245.
Lange JH, Coolen HK, van Stuivenberg HH, Dijksman JA, Herremans AH, Ronken E, Keizer HG, Tipker
K, McCreary AC, Veerman W, Wals HC, Stork B,
Verveer PC, den Hartog AP, de Jong NM, Adolfs TJ,
Hoogendoorn J, Kruse CG (2004) Synthesis, biological properties, and molecular modeling investigations of
novel 3,4-diarylpyrazolines as potent and selective CB(1)
cannabinoid receptor antagonists. J Med Chem 47, 627643.
Lange JH, van Stuivenberg HH, Coolen HK, Adolfs
TJ, McCreary AC, Keizer HG, Wals HC, Veerman W,
Borst AJ, de LW, Verveer PC, Kruse CG (2005) Bioisosteric replacements of the pyrazole moiety of rimonabant:
Synthesis, biological properties, and molecular modeling
investigations of thiazoles, triazoles, and imidazoles as
potent and selective CB1 cannabinoid receptor antagonists. J Med Chem 48, 1823-1838.
Lange JH, Coolen HK, van der Neut MA, Borst AJ, Stork
B, Verveer PC, Kruse CG (2010) Design, synthesis, biological properties, and molecular modeling investigations
of novel tacrine derivatives with a combination of acetylcholinesterase inhibition and cannabinoid CB1 receptor
antagonism. J Med Chem 53, 1338-1346.
Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A,
Hillard CJ, Romero J (2003) Cannabinoid CB2 receptors
and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s
disease brains. J Neurosci 23, 11136-11141.
Rampa A, Bartolini M, Bisi A, Belluti F, Gobbi S,
Andrisano V, Ligresti A, Di Marzo V (2012) The first dual
ChE/FAAH inhibitors: New perspectives for Alzheimer’s
disease? ACS Med Chem Lett 3, 182-186.
Lynch AM, Loane DJ, Minogue AM, Clarke RM, Kilroy D, Nally RE, Roche OJ, O’Connell F, Lynch MA
(2007) Eicosapentaenoic acid confers neuroprotection in
the amyloid-beta challenged aged hippocampus. Neurobiol Aging 28, 845-855.
Minogue AM, Lynch AM, Loane DJ, Herron CE, Lynch
MA (2007) Modulation of amyloid-beta-induced and
age-associated changes in rat hippocampus by eicosapentaenoic acid. J Neurochem 103, 914-926.
Hashimoto M, Hossain S, Tanabe Y, Kawashima A, Harada
T, Yano T, Mizuguchi K, Shido O (2009) The protective
effect of dietary eicosapentaenoic acid against impairment
of spatial cognition learning ability in rats infused with
amyloid beta(1-40). J Nutr Biochem 20, 965-973.
Yehuda S (2012) Polyunsaturated fatty acids as putative
cognitive enhancers. Med Hypotheses 79, 456-461.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[450]
[451]
[452]
[453]
[454]
[455]
[456]
[457]
[458]
[459]
[460]
[461]
[462]
Petroianu G, Arafat K, Sasse BC, Stark H (2006) Multiple
enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Pharmazie 61, 179182.
Incerti M, Flammini L, Saccani F, Morini G, Comini
M, Coruzzi M, Barocelli E, Ballabeni V, Bertoni S
(2010) Dual-acting drugs: An in vitro study of nonimidazole histamine H3 receptor antagonists combining
anticholinesterase activity. ChemMedChem 5, 1143-1149.
Huang W, Tang L, Shi Y, Huang S, Xu L, Sheng R,
Wu P, Li J, Zhou N, Hu Y (2011) Searching for the
Multi-Target-Directed Ligands against Alzheimer’s disease: Discovery of quinoxaline-based hybrid compounds
with AChE, H(3)R and BACE 1 inhibitory activities.
Bioorg Med Chem 19, 7158-7167.
Saura J, Luque JM, Cesura AM, Da PM, Chan-Palay
V, Huber G, Loffler J, Richards JG (1994) Increased
monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme
radioautography. Neuroscience 62, 15-30.
Fink DM, Palermo MG, Bores GM, Huger FP, Kurys BE,
Merriman MC, Olsen GE, Petko W, O’Malley GJ (1996)
Imino 1,2,3,4-tetrahydrocylopent [b]indole carbamates as
dual inhibitors of acetylcholinesterase and monoamine
oxidase. Bioorg Med Chem Lett 6, 625-630.
Bruhlmann C, Ooms F, Carrupt PA, Testa B, Catto M,
Leonetti F, Altomare C, Carotti A (2001) Coumarins
derivatives as dual inhibitors of acetylcholinesterase and
monoamine oxidase. J Med Chem 44, 3195-3198.
Weinstock M, Bejar C, Wang RH, Poltyrev T, Gross A,
Finberg JP, Youdim MB (2000) TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase
inhibitory activities for the treatment of Alzheimer’s disease. J Neural Transm Suppl 60, 157-169.
Weinstock M, Kirschbaum-Slager N, Lazarovici P, Bejar
C, Youdim MB, Shoham S (2001) Neuroprotective effects
of novel cholinesterase inhibitors derived from rasagiline
as potential anti-Alzheimer drugs. Ann N Y Acad Sci 939,
148-161.
Weinstock M, Luques L, Poltyrev T, Bejar C, Shoham S
(2011) Ladostigil prevents age-related glial activation and
spatial memory deficits in rats. Neurobiol Aging 32, 10691078.
Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D,
Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T,
Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross
A, Friedman R, Razin M, Huang W, Krais B, Chorev M,
Youdim MB, Weinstock M (2002) Novel dual inhibitors
of AChE and MAO derived from hydroxy aminoindan
and phenethylamine as potential treatment for Alzheimer’s
disease. J Med Chem 45, 5260-5279.
Sagi Y, Weinstock M, Youdim MB (2003) Attenuation of
MPTP-induced dopaminergic neurotoxicity by TV3326, a
cholinesterase-monoamine oxidase inhibitor. J Neurochem
86, 290-297.
Youdim MB, Amit T, Bar-Am O, Weinstock M,
Yogev-Falach M (2003) Amyloid processing and signal transduction properties of antiparkinson-antialzheimer
neuroprotective drugs rasagiline and TV3326. Ann N Y
Acad Sci 993, 378-386.
Youdim MB, Amit T, Bar-Am O, Weinreb O, YogevFalach M (2006) Implications of co-morbidity for etiology
and treatment of neurodegenerative diseases with multifunctional neuroprotective-neurorescue drugs; ladostigil.
Neurotox Res 10, 181-192.
[463]
[464]
[465]
[466]
[467]
[468]
[469]
[470]
[471]
[472]
[473]
[474]
[475]
611
Youdim MB (2006) The path from anti Parkinson drug
selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr
Alzheimer Res 3, 541-550.
Poltyrev T, Gorodetsky E, Bejar C, Schorer-Apelbaum
D, Weinstock M (2005) Effect of chronic treatment with
ladostigil (TV-3326) on anxiogenic and depressive-like
behaviour and on activity of the hypothalamic-pituitaryadrenal axis in male and female prenatally stressed rats.
Psychopharmacology (Berl) 181, 118-125.
Yogev-Falach M, Bar-Am O, Amit T, Weinreb O, Youdim
MB (2006) A multifunctional, neuroprotective drug,
ladostigil (TV3326), regulates holo-APP translation and
processing. FASEB J 20, 2177-2179.
Bar-Am O, Weinreb O, Amit T, Youdim MB (2009) The
novel cholinesterase-monoamine oxidase inhibitor and
antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats. J Mol Neurosci 37, 135145.
Bar-Am O, Amit T, Weinreb O, Youdim MB, Mandel S
(2010) Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein
precursor: Involvement of MAPK and PKC activation.
J Alzheimers Dis 21, 361-371.
Weinreb O, Amit T, Bar-Am O, Yogev-Falach M, Youdim
MB (2008) The neuroprotective mechanism of action of
the multimodal drug ladostigil. Front Biosci 13, 51315137.
Weinreb O, Bar-Am O, Amit T, Drigues N, Sagi Y,
Youdim MB (2008) The neuroprotective effect of ladostigil
against hydrogen peroxide-mediated cytotoxicity. Chem
Biol Interact 175, 318-326.
Weinreb O, Mandel S, Bar-Am O, Yogev-Falach M,
vramovich-Tirosh Y, Amit T, Youdim MB (2009) Multifunctional neuroprotective derivatives of rasagiline as
anti-Alzheimer’s disease drugs. Neurotherapeutics 6, 163174.
Weinreb O, Amit T, Bar-Am O, Youdim MB (2011) A
novel anti-Alzheimer’s disease drug, ladostigil neuroprotective, multimodal brain-selective monoamine oxidase
and cholinesterase inhibitor. Int Rev Neurobiol 100, 191215.
Weinreb O, Amit T, Bar-Am O, Youdim MB (2012)
Ladostigil: A novel multimodal neuroprotective drug with
cholinesterase and brain-selective monoamine oxidase
inhibitory activities for Alzheimer’s disease treatment.
Curr Drug Targets 13, 483-494.
Samadi A, Chioua M, Bolea I, de Los RC, Iriepa I,
Moraleda I, Bastida A, Esteban G, Unzeta M, Galvez
E, Marco-Contelles J (2011) Synthesis, biological assessment and molecular modeling of new multipotent MAO
and cholinesterase inhibitors as potential drugs for the
treatment of Alzheimer’s disease. Eur J Med Chem 46,
4665-4668.
Samadi A, de Los RC, Bolea I, Chioua M, Iriepa I,
Moraleda I, Bartolini M, Andrisano V, Galvez E, Valderas
C, Unzeta M, Marco-Contelles J (2012) Multipotent
MAO and cholinesterase inhibitors for the treatment of
Alzheimer’s disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted
alkyl and cycloalkyl propargyl amine. Eur J Med Chem
52, 251-262.
Bolea I, Juarez-Jimenez J, de los RC, Chioua M,
Pouplana R, Luque FJ, Unzeta M, Marco-Contelles J,
Samadi A (2011) Synthesis, biological evaluation, and
612
[476]
[477]
[478]
[479]
[480]
[481]
[482]
[483]
[484]
[485]
[486]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
molecular modeling of donepezil and N-[(5-(benzyloxy)1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1amine hybrids as new multipotent cholinesterase/
monoamine oxidase inhibitors for the treatment of
Alzheimer’s disease. J Med Chem 54, 8251-8270.
Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik
ZI, Warshawsky A, Youdim MB, Fridkin M (2005)
Design, synthesis, and evaluation of novel bifunctional
iron-chelators as potential agents for neuroprotection in
Alzheimer’s, Parkinson’s, and other neurodegenerative
diseases. Bioorg Med Chem 13, 773-783.
Zheng H, Youdim MB, Fridkin M (2009) Site-activated
multifunctional chelator with acetylcholinesterase and
neuroprotective-neurorestorative moieties for Alzheimer’s
therapy. J Med Chem 52, 4095-4098.
Zheng H, Fridkin M, Youdim MB (2012) Novel chelators targeting cell cycle arrest, acetylcholinesterase, and
monoamine oxidase for Alzheimer’s therapy. Curr Drug
Targets 13, 1089-1106.
Meng FC, Mao F, Shan WJ, Qin F, Huang L, Li XS (2012)
Design, synthesis, and evaluation of indanone derivatives as acetylcholinesterase inhibitors and metal-chelating
agents. Bioorg Med Chem Lett 22, 4462-4466.
Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi
ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR,
Melchiorre C (2008) Inhibition of acetylcholinesterase,
beta-amyloid aggregation, and NMDA receptors in
Alzheimer’s disease: A promising direction for the multitarget-directed ligands gold rush. J Med Chem 51,
4381-4384.
Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wunsch
B, Heilmann J, Lehmann J, Winckler T (2010) Bivalent
beta-carbolines as potential multitarget anti-Alzheimer
agents. J Med Chem 53, 3611-3617.
Le Texier L, Favre E, Redeuilh C, Blavet N, Bellahsene
T, Dive G, Pirotzky E, Godfroid JJ (1996) Structureactivity relationships in platelet-activating factor (PAF).
7. Tetrahydrofuran derivatives as dual PAF antagonists
and acetylcholinesterase inhibitors. Synthesis and PAFantagonistic activity. J Lipid Mediat Cell Signal 13,
189-205.
Le Texier L, Favre E, Ronzani N, Massicot F, Blavet
N, Pirotzky E, Godfroid JJ (1996) Structure-activity
relationships in platelet-activating factor (PAF). 8.
Tetrahydrofuran derivatives as dual PAF antagonists and
acetylcholinesterase inhibitors: Anti-acetylcholinesterase
activity and comparative SAR. J Lipid Mediat Cell Signal
13, 207-222.
Ezoulin MJ, Li J, Wu G, Dong CZ, Ombetta JE, Chen
HZ, Massicot F, Heymans F (2005) Differential effect of
PMS777, a new type of acetylcholinesterase inhibitor, and
galanthamine on oxidative injury induced in human neuroblastoma SK-N-SH cells. Neurosci Lett 389, 61-65.
Ezoulin MJ, Dong CZ, Liu Z, Li J, Chen HZ, Heymans F, Lelievre L, Ombetta JE, Massicot F (2006)
Study of PMS777, a new type of acetylcholinesterase
inhibitor, in human HepG2 cells. Comparison with tacrine
and galanthamine on oxidative stress and mitochondrial
impairment. Toxicol In Vitro 20, 824-831.
Ezoulin MJ, Liu Z, Dutertre-Catella H, Wu G, Dong CZ,
Heymans F, Ombetta JE, Rat P, Massicot F (2007) A
new acetylcholinesterase inhibitor with anti-PAF activity
modulates oxidative stress and pro-inflammatory mediators release in stimulated RAW 264.7 macrophage cells.
[487]
[488]
[489]
[490]
[491]
[492]
[493]
[494]
[495]
[496]
[497]
Comparison with tacrine. Int Immunopharmacol 7, 16851694.
Li J, Huang H, Miezan Ezoulin JM, Gao XL, Massicot F,
Dong CZ, Heymans F, Chen HZ (2007) Pharmacological
profile of PMS777, a new AChE inhibitor with PAF antagonistic activity. Int J Neuropsychopharmacol 10, 21-29.
Li J, Shao B, Zhu L, Cui Y, Dong C, Miezan Ezoulin JM,
Gao X, Ren Q, Heymans F, Chen H (2008) PMS777, a bisinteracting ligand for PAF receptor antagonism and AChE
inhibition, attenuates PAF-induced neurocytotoxicity in
SH-SY5Y cells. Cell Mol Neurobiol 28, 125-136.
Li J, Hu J, Shao B, Zhou W, Cui Y, Dong C, Ezoulin JM,
Zhu X, Ding W, Heymans F, Chen H (2009) Protection
of PMS777, a new AChE inhibitor with PAF antagonism,
against amyloid-beta-induced neuronal apoptosis and neuroinflammation. Cell Mol Neurobiol 29, 589-595.
Yang HQ, Sun ZK, Zhao YX, Pan J, Ba MW, Lu GQ,
Ding JQ, Chen HZ, Chen SD (2009) PMS777, a new
cholinesterase inhibitor with anti-platelet activated factor
activity, regulates amyloid precursor protein processing in
vitro. Neurochem Res 34, 528-535.
Miezan Ezoulin JM, Shao BY, Xia Z, Xie Q, Li J, Cui
YY, Wang H, Dong CZ, Zhao YX, Massicot F, Qiu ZB,
Heymans F, Chen HZ (2009) Novel piperazine derivative
PMS1339 exhibits tri-functional properties and cognitive
improvement in mice. Int J Neuropsychopharmacol 12,
1409-1419.
Abe Y, Aoyagi A, Hara T, Abe K, Yamazaki R, Kumagae
Y, Naruto S, Koyama K, Marumoto S, Tago K, Toda N,
Takami K, Yamada N, Ori M, Kogen H, Kaneko T (2003)
Pharmacological characterization of RS-1259, an orally
active dual inhibitor of acetylcholinesterase and serotonin
transporter, in rodents: Possible treatment of Alzheimer’s
disease. J Pharmacol Sci 93, 95-105.
Toda N, Tago K, Marumoto S, Takami K, Ori M, Yamada
N, Koyama K, Naruto S, Abe K, Yamazaki R, Hara T,
Aoyagi A, Abe Y, Kaneko T, Kogen H (2003) Design, synthesis and structure-activity relationships of dual inhibitors
of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer’s disease. Bioorg Med Chem 11,
1935-1955.
Toda N, Tago K, Marumoto S, Takami K, Ori M, Yamada
N, Koyama K, Naruto S, Abe K, Yamazaki R, Hara T, Aoyagi A, Abe Y, Kaneko T, Kogen H (2003) A conformational
restriction approach to the development of dual inhibitors
of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer’s disease. Bioorg Med Chem 11,
4389-4415.
Toda N, Kaneko T, Kogen H (2010) Development of an
efficient therapeutic agent for Alzheimer’s disease: Design
and synthesis of dual inhibitors of acetylcholinesterase and
serotonin transporter. Chem Pharm Bull (Tokyo) 58, 273287.
Lecanu L, Tillement L, McCourty A, Rammouz
G, Yao W, Greeson J, Papadopoulos V (2010)
Dimethyl-carbamic acid 2,3-Bis-Dimethylcarbamoyloxy6-(4-Ethyl-Piperazine-1-Carbonyl)-phenyl ester: A novel
multi-target therapeutic approach to neuroprotection. Med
Chem 6, 123-140.
Panza F, Solfrizzi V, Frisardi V, Capurso C, D’Introno A,
Colacicco AM, Vendemiale G, Capurso A, Imbimbo BP
(2009) Disease-modifying approach to the treatment of
Alzheimer’s disease: From alpha-secretase activators to
gamma-secretase inhibitors and modulators. Drugs Aging
26, 537-555.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[498]
[499]
[500]
[501]
[502]
[503]
[504]
[505]
[506]
[507]
[508]
[509]
[510]
[511]
[512]
Vincent B, Govitrapong P (2011) Activation of the alphasecretase processing of AbetaPP as a therapeutic approach
in Alzheimer’s disease. J Alzheimers Dis 24(Suppl 2), 7594.
Frisardi V, Solfrizzi V, Imbimbo PB, Capurso C, D’Introno
A, Colacicco AM, Vendemiale G, Seripa D, Pilotto A,
Capurso A, Panza F (2010) Towards disease-modifying
treatment of Alzheimer’s disease: Drugs targeting betaamyloid. Curr Alzheimer Res 7, 40-55.
Endres K, Fahrenholz F (2012) Regulation of alphasecretase ADAM10 expression and activity. Exp Brain Res
217, 343-352.
Postina R (2012) Activation of alpha-secretase cleavage.
J Neurochem 120(Suppl 1), 46-54.
Epis R, Marcello E, Gardoni F, Luca MD (2012) Alpha,
beta-and gamma-secretases in alzheimer’s disease. Front
Biosci (Schol Ed) 4, 1126-1150.
Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer
A, Drouin D, Schweighoffer F, Desire L (2008) Etazolate, a neuroprotective drug linking GABA(A) receptor
pharmacology to amyloid precursor protein processing.
J Neurochem 106, 392-404.
Drott J, Desire L, Drouin D, Pando M, Haun F (2010)
Etazolate improves performance in a foraging and homing
task in aged rats. Eur J Pharmacol 634, 95-100.
Vellas B, Sol O, Snyder PJ, Ousset PJ, Haddad R, Maurin
M, Lemarie JC, Desire L, Pando MP (2011) EHT0202
in Alzheimer’s disease: A 3-month, randomized, placebocontrolled, double-blind study. Curr Alzheimer Res 8, 203212.
Panza F, Solfrizzi V, Frisardi V, Imbimbo BP, Capurso
C, D’Introno A, Colacicco AM, Seripa D, Vendemiale G,
Capurso A, Pilotto A (2009) Beyond the neurotransmitterfocused approach in treating Alzheimer’s disease: Drugs
targeting beta-amyloid and tau protein. Aging Clin Exp Res
21, 386-406.
Ruan BF, Zhu HL (2012) The chemistry and biology of
the bryostatins: Potential PKC inhibitors in clinical development. Curr Med Chem 19, 2652-2664.
Vassar R, Kovacs DM, Yan R, Wong PC (2009) The
beta-secretase enzyme BACE in health and Alzheimer’s
disease: Regulation, cell biology, function, and therapeutic
potential. J Neurosci 29, 12787-12794.
Vassar R, Kandalepas PC (2011) The beta-secretase
enzyme BACE1 as a therapeutic target for Alzheimer’s
disease. Alzheimers Res Ther 3, 20.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz
EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R,
Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski
MA, Biere AL, Curran E, Burgess T, Louis JC, Collins
F, Treanor J, Rogers G, Citron M (1999) Beta-secretase
cleavage of Alzheimer’s amyloid precursor protein by the
transmembrane aspartic protease BACE. Science 286, 735741.
Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO,
Bennett BD, Kahn S, Ross S, Burgess T, Katta V, Rogers G,
Vassar R, Citron M (2000) Characterization of Alzheimer’s
beta -secretase protein BACE. A pepsin family member
with unusual properties. J Biol Chem 275, 21099-21106.
Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello
R, Davis D, Doan M, Dovey HF, Frigon N, Hong J,
Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D,
Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J,
McConlogue L, John V (1999) Purification and cloning
[513]
[514]
[515]
[516]
[517]
[518]
[519]
[520]
[521]
[522]
[523]
[524]
[525]
[526]
[527]
613
of amyloid precursor protein beta-secretase from human
brain. Nature 402, 537-540.
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC,
Pauley AM, Brashier JR, Stratman NC, Mathews WR,
Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME (1999) Membrane-anchored aspartyl
protease with Alzheimer’s disease beta-secretase activity.
Nature 402, 533-537.
Hussain I, Powell D, Howlett DR, Tew DG, Meek TD,
Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan
DM, Smith TS, Simmons DL, Walsh FS, Dingwall C,
Christie G (1999) Identification of a novel aspartic protease
(Asp 2) as beta-secretase. Mol Cell Neurosci 14, 419-427.
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK,
Zhang XC, Tang J (2000) Structure of the protease domain
of memapsin 2 (beta-secretase) complexed with inhibitor.
Science 290, 150-153.
Citron M (2004) Beta-secretase inhibition for the treatment
of Alzheimer’s disease–promise and challenge. Trends
Pharmacol Sci 25, 92-97.
Venugopal C, Demos CM, Rao KS, Pappolla MA,
Sambamurti K (2008) Beta-secretase: Structure, function,
and evolution. CNS Neurol Disord Drug Targets 7, 278294.
Murphy T, Yip A, Brayne C, Easton D, Evans JG, Xuereb
J, Cairns N, Esiri MM, Rubinsztein DC (2001) The BACE
gene: Genomic structure and candidate gene study in lateonset Alzheimer’s disease. Neuroreport 12, 631-634.
Hunt CE, Turner AJ (2009) Cell biology, regulation and
inhibition of beta-secretase (BACE-1). FEBS J 276, 18451859.
Ahmed RR, Holler CJ, Webb RL, Li F, Beckett TL,
Murphy MP (2010) BACE1 and BACE2 enzymatic activities in Alzheimer’s disease. J Neurochem 112, 1045-1053.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S,
Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass
C (2006) Control of peripheral nerve myelination by the
beta-secretase BACE1. Science 314, 664-666.
Willem M, Lammich S, Haass C (2009) Function, regulation and therapeutic properties of beta-secretase (BACE1).
Semin Cell Dev Biol 20, 175-182.
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK,
Zhang XC, Tang J (2000) Structure of the protease domain
of memapsin 2 (beta-secretase) complexed with inhibitor.
Science 290, 150-153.
Hong L, Turner RT III, Koelsch G, Shin D, Ghosh
AK, Tang J (2002) Crystal structure of memapsin 2
(beta-secretase) in complex with an inhibitor OM00-3.
Biochemistry 41, 10963-10967.
Patel S, Vuillard L, Cleasby A, Murray CW, Yon J (2004)
Apo and inhibitor complex structures of BACE (betasecretase). J Mol Biol 343, 407-416.
Rojo I, Martin JA, Broughton H, Timm D, Erickson J, Yang
HC, McCarthy JR (2006) Macrocyclic peptidomimetic
inhibitors of beta-secretase (BACE): First X-ray structure
of a macrocyclic peptidomimetic-BACE complex. Bioorg
Med Chem Lett 16, 191-195.
Barrow JC, Stauffer SR, Rittle KE, Ngo PL, Yang Z,
Selnick HG, Graham SL, Munshi S, McGaughey GB,
Holloway MK, Simon AJ, Price EA, Sankaranarayanan
S, Colussi D, Tugusheva K, Lai MT, Espeseth AS, Xu M,
Huang Q, Wolfe A, Pietrak B, Zuck P, Levorse DA, Hazuda
D, Vacca JP (2008) Discovery and X-ray crystallographic
analysis of a spiropiperidine iminohydantoin inhibitor of
beta-secretase. J Med Chem 51, 6259-6262.
614
[528]
[529]
[530]
[531]
[532]
[533]
[534]
[535]
[536]
[537]
[538]
[539]
[540]
[541]
[542]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T,
Nukina N (2008) Crystal structure of an active form of
BACE1, an enzyme responsible for amyloid beta protein
production. Mol Cell Biol 28, 3663-3671.
Roberds SL, Anderson J, Basi G, Bienkowski MJ,
Branstetter DG, Chen KS, Freedman SB, Frigon NL,
Games D, Hu K, Johnson-Wood K, Kappenman KE,
Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R,
Nichols NF, Power M, Robertson DW, Schenk D, Schoor
M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L
(2001) BACE knockout mice are healthy despite lacking
the primary beta-secretase activity in brain: Implications
for Alzheimer’s disease therapeutics. Hum Mol Genet 10,
1317-1324.
Harrison SM, Harper AJ, Hawkins J, Duddy G, Grau E,
Pugh PL, Winter PH, Shilliam CS, Hughes ZA, Dawson
LA, Gonzalez MI, Upton N, Pangalos MN, Dingwall C
(2003) BACE1 (beta-secretase) transgenic and knockout
mice: Identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 24, 646-655.
Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin
SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1
deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron
41, 27-33.
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson
PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D,
Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale
T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen
OA, Jonsson EG, Palotie A, Behrens TW, Magnusson
OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K
(2012) A mutation in APP protects against Alzheimer’s
disease and age-related cognitive decline. Nature 488,
96-99.
Callaway E (2012) Gene mutation defends against
Alzheimer’s disease. Nature 487, 153.
Dingwall C (2001) Spotlight on BACE: The secretases as
targets for treatment in Alzheimer disease. J Clin Invest
108, 1243-1246.
Vassar R (2001) The beta-secretase, BACE: A prime drug
target for Alzheimer’s disease. J Mol Neurosci 17, 157170.
Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D,
Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G,
Ermolieff J, Tang J (2001) Structure-based design: Potent
inhibitors of human brain memapsin 2 (beta-secretase).
J Med Chem 44, 2865-2868.
Citron M (2002) Beta-secretase as a target for the treatment
of Alzheimer’s disease. J Neurosci Res 70, 373-379.
Citron M (2002) Emerging Alzheimer’s disease therapies:
Inhibition of beta-secretase. Neurobiol Aging 23, 10171022.
Dewachter I, Van Leuven F (2002) Secretases as targets
for the treatment of Alzheimer’s disease: The prospects.
Lancet Neurol 1, 409-416.
Ghosh AK, Hong L, Tang J (2002) Beta-secretase as a
therapeutic target for inhibitor drugs. Curr Med Chem 9,
1135-1144.
Hong L, Turner RT III, Koelsch G, Ghosh AK, Tang J
(2002) Memapsin 2 (beta-secretase) as a therapeutic target.
Biochem Soc Trans 30, 530-534.
Roggo S (2002) Inhibition of BACE, a promising approach
to Alzheimer’s disease therapy. Curr Top Med Chem 2,
359-370.
[543]
[544]
[545]
[546]
[547]
[548]
[549]
[550]
[551]
[552]
[553]
[554]
[555]
[556]
[557]
[558]
[559]
[560]
[561]
[562]
[563]
Vassar R (2002) Beta-secretase (BACE) as a drug target for
Alzheimer’s disease. Adv Drug Deliv Rev 54, 1589-1602.
Conway KA, Baxter EW, Felsenstein KM, Reitz AB
(2003) Emerging beta-amyloid therapies for the treatment
of Alzheimer’s disease. Curr Pharm Des 9, 427-447.
John V, Beck JP, Bienkowski MJ, Sinha S, Heinrikson
RL (2003) Human beta-secretase (BACE) and BACE
inhibitors. J Med Chem 46, 4625-4630.
Koelsch G, Turner RT III, Hong L, Ghosh AK, Tang J
(2003) Memapsin 2, a drug target for Alzheimer’s disease.
Biochem Soc Symp 70, 213-220.
Tang J, Ghosh AK, Hong L, Koelsch G, Turner RT III,
Chang W (2003) Study of memapsin 2 (beta-secretase) and
strategy of inhibitor design. J Mol Neurosci 20, 299-304.
Cumming JN, Iserloh U, Kennedy ME (2004) Design and
development of BACE-1 inhibitors. Curr Opin Drug Discov Devel 7, 536-556.
Hussain I (2004) The potential for BACE1 inhibitors in
the treatment of Alzheimer’s disease. IDrugs 7, 653-658.
Vassar R (2004) BACE1: The beta-secretase enzyme in
Alzheimer’s disease. J Mol Neurosci 23, 105-114.
Thompson LA, Bronson JJ, Zusi FC (2005) Progress in
the discovery of BACE inhibitors. Curr Pharm Des 11,
3383-3404.
Vassar R (2005) beta-Secretase, APP and Abeta in
Alzheimer’s disease. Subcell Biochem 38, 79-103.
Durham TB, Shepherd TA (2006) Progress toward the discovery and development of efficacious BACE inhibitors.
Curr Opin Drug Discov Devel 9, 776-791.
Guo T, Hobbs DW (2006) Development of BACE1
inhibitors for Alzheimer’s disease. Curr Med Chem 13,
1811-1829.
John V (2006) Human beta-secretase (BACE) and BACE
inhibitors: Progress report. Curr Top Med Chem 6, 569578.
Schmidt B, Baumann S, Braun HA, Larbig G (2006)
Inhibitors and modulators of beta- and gamma-secretase.
Curr Top Med Chem 6, 377-392.
Schmidt B, Baumann S, Narlawar R, Braun HA, Larbig
G (2006) Modulators and inhibitors of gamma- and betasecretases. Neurodegener Dis 3, 290-297.
Evin G, Kenche VB (2007) BACE inhibitors as potential therapeutics for Alzheimer’s disease. Recent Pat CNS
Drug Discov 2, 188-199.
Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu
X, Chang W, Weerasena V, Turner R, Koelsch G, Bilcer
G, Tang J (2007) Design, synthesis, and X-ray structure of
potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem
50, 2399-2407.
Ghosh AK, Bilcer G, Hong L, Koelsch G, Tang J (2007)
Memapsin 2 (beta-secretase) inhibitor drug, between fantasy and reality. Curr Alzheimer Res 4, 418-422.
Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni S, Xu
X, Miller HB, Reddy DS, Weerasena V, Turner R, Chang
W, Koelsch G, Tang J (2008) Potent memapsin 2 (betasecretase) inhibitors: Design, synthesis, protein-ligand Xray structure, and in vivo evaluation. Bioorg Med Chem
Lett 18, 1031-1036.
Ghosh AK, Kumaragurubaran N, Hong L, Koelsh G, Tang
J (2008) Memapsin 2 (beta-secretase) inhibitors: Drug
development. Curr Alzheimer Res 5, 121-131.
Ghosh AK, Gemma S, Tang J (2008) beta-Secretase as
a therapeutic target for Alzheimer’s disease. Neurotherapeutics 5, 399-408.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[564]
[565]
[566]
[567]
[568]
[569]
[570]
[571]
[572]
[573]
[574]
[575]
[576]
[577]
[578]
[579]
[580]
[581]
[582]
Albert JS (2009) Progress in the development of betasecretase inhibitors for Alzheimer’s disease. Prog Med
Chem 48, 133-161.
Ghosh AK (2009) Harnessing nature’s insight: Design
of aspartyl protease inhibitors from treatment of drugresistant HIV to Alzheimer’s disease. J Med Chem 52,
2163-2176.
Huang WH, Sheng R, Hu YZ (2009) Progress in the
development of nonpeptidomimetic BACE 1 inhibitors for
Alzheimer’s disease. Curr Med Chem 16, 1806-1820.
Silvestri R (2009) Boom in the development of nonpeptidic beta-secretase (BACE1) inhibitors for the
treatment of Alzheimer’s disease. Med Res Rev 29, 295338.
Stachel SJ (2009) Progress toward the development of a
viable BACE-1 inhibitor. Drug Dev Res 70, 101-110.
Tomita T (2009) Secretase inhibitors and modulators for
Alzheimer’s disease treatment. Expert Rev Neurother 9,
661-679.
De Strooper B, Vassar R, Golde T (2010) The secretases:
Enzymes with therapeutic potential in Alzheimer disease.
Nat Rev Neurol 6, 99-107.
Klaver DW, Wilce MC, Cui H, Hung AC, Gasperini R,
Foa L, Small DH (2010) Is BACE1 a suitable therapeutic
target for the treatment of Alzheimer’s disease? Current
strategies and future directions. Biol Chem 391, 849-859.
Luo X, Yan R (2010) Inhibition of BACE1 for therapeutic
use in Alzheimer’s disease. Int J Clin Exp Pathol 3, 618628.
Marks N, Berg MJ (2010) BACE and gamma-secretase
characterization and their sorting as therapeutic targets to
reduce amyloidogenesis. Neurochem Res 35, 181-210.
Evin G, Barakat A, Masters CL (2010) BACE: Therapeutic
target and potential biomarker for Alzheimer’s disease. Int
J Biochem Cell Biol 42, 1923-1926.
Evin G, Lessene G, Wilkins S (2011) BACE inhibitors as
potential drugs for the treatment of Alzheimer’s disease:
Focus on bioactivity. Recent Pat CNS Drug Discov 6, 91106.
Mancini F, De Simone A, Andrisano V (2011) Betasecretase as a target for Alzheimer’s disease drug
discovery: An overview of in vitro methods for characterization of inhibitors. Anal Bioanal Chem 400, 1979-1996.
Woo HN, Baik SH, Park JS, Gwon AR, Yang S, Yun
YK, Jo DG (2011) Secretases as therapeutic targets for
Alzheimer’s disease. Biochem Biophys Res Commun 404,
10-15.
Tresadern G, Delgado F, Delgado O, Gijsen H, Macdonald GJ, Moechars D, Rombouts F, Alexander R, Spurlino
J, Van GM, Vega JA, Trabanco AA (2011) Rational design
and synthesis of aminopiperazinones as beta-secretase
(BACE) inhibitors. Bioorg Med Chem Lett 21, 72557260.
Ghosh AK, Brindisi M, Tang J (2012) Developing betasecretase inhibitors for treatment of Alzheimer’s disease.
J Neurochem 120(Suppl 1), 71-83.
Kandalepas PC, Vassar R (2012) Identification and biology
of beta-secretase. J Neurochem 120(Suppl 1), 55-61.
Zhu Z (2012) Iminoheterocycle as a druggable motif:
BACE1 inhibitors and beyond. Trends Pharmacol Sci 33,
233-240.
Hu J, Cwi CL, Smiley DL, Timm D, Erickson JA, McGee
JE, Yang HC, Mendel D, May PC, Shapiro M, McCarthy
JR (2003) Design and synthesis of statine-containing
BACE inhibitors. Bioorg Med Chem Lett 13, 4335-4339.
[583]
[584]
[585]
[586]
[587]
[588]
[589]
[590]
[591]
[592]
[593]
615
Chen SH, Lamar J, Guo D, Kohn T, Yang HC, McGee J,
Timm D, Erickson J, Yip Y, May P, McCarthy J (2004)
P3 cap modified Phe*-Ala series BACE inhibitors. Bioorg
Med Chem Lett 14, 245-250.
Lamar J, Hu J, Bueno AB, Yang HC, Guo D, Copp JD,
McGee J, Gitter B, Timm D, May P, McCarthy J, Chen SH
(2004) Phe*-Ala-based pentapeptide mimetics are BACE
inhibitors: P2 and P3 SAR. Bioorg Med Chem Lett 14,
239-243.
Vidal P, Timm D, Broughton H, Chen SH, Martin JA,
Rivera-Sagredo A, McCarthy JR, Shapiro MJ, Espinosa JF
(2005) Preorganization of the hydroxyethylene dipeptide
isostere: The preferred conformation in solution resembles the conformation bound to BACE. J Med Chem 48,
7623-7627.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM,
Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM, Stout SL, Timm DE, Smith LE, Gonzales CR,
Nakano M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD,
Calligaro DO, Cocke PJ, Greg HD, Friedrich S, Citron M,
Audia JE (2011) Robust central reduction of amyloid-beta
in humans with an orally available, non-peptidic betasecretase inhibitor. J Neurosci 31, 16507-16516.
Burt J (2010) American Chemical Society - 240th national
meeting - chemistry for preventing and combating disease:
Part 1. IDrugs 13, 669-672.
Cumming JN, Le TX, Babu S, Carroll C, Chen X, Favreau
L, Gaspari P, Guo T, Hobbs DW, Huang Y, Iserloh U,
Kennedy ME, Kuvelkar R, Li G, Lowrie J, McHugh NA,
Ozgur L, Pan J, Parker EM, Saionz K, Stamford AW,
Strickland C, Tadesse D, Voigt J, Wang L, Wu Y, Zhang L,
Zhang Q (2008) Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors. Bioorg Med
Chem Lett 18, 3236-3241.
Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker
EM, Strickland C, Voigt J (2008) Potent pyrrolidine- and
piperidine-based BACE-1 inhibitors. Bioorg Med Chem
Lett 18, 414-417.
Iserloh U, Pan J, Stamford AW, Kennedy ME, Zhang Q,
Zhang L, Parker EM, McHugh NA, Favreau L, Strickland C, Voigt J (2008) Discovery of an orally efficaceous
4-phenoxypyrrolidine-based BACE-1 inhibitor. Bioorg
Med Chem Lett 18, 418-422.
Wang YS, Strickland C, Voigt JH, Kennedy ME, Beyer
BM, Senior MM, Smith EM, Nechuta TL, Madison VS,
Czarniecki M, McKittrick BA, Stamford AW, Parker EM,
Hunter JC, Greenlee WJ, Wyss DF (2010) Application
of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library
design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1)
inhibitors. J Med Chem 53, 942-950.
Zhu Z, Sun ZY, Ye Y, Voigt J, Strickland C, Smith EM,
Cumming J, Wang L, Wong J, Wang YS, Wyss DF, Chen
X, Kuvelkar R, Kennedy ME, Favreau L, Parker E, McKittrick BA, Stamford A, Czarniecki M, Greenlee W, Hunter
JC (2010) Discovery of cyclic acylguanidines as highly
potent and selective beta-site amyloid cleaving enzyme
(BACE) inhibitors: Part I–inhibitor design and validation.
J Med Chem 53, 951-965.
Cumming JN, Smith EM, Wang L, Misiaszek J, Durkin
J, Pan J, Iserloh U, Wu Y, Zhu Z, Strickland C, Voigt J,
Chen X, Kennedy ME, Kuvelkar R, Hyde LA, Cox K,
Favreau L, Czarniecki MF, Greenlee WJ, McKittrick BA,
616
[594]
[595]
[596]
[597]
[598]
[599]
[600]
[601]
[602]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Parker EM, Stamford AW (2012) Structure based design
of iminohydantoin BACE1 inhibitors: Identification of an
orally available, centrally active BACE1 inhibitor. Bioorg
Med Chem Lett 22, 2444-2449.
Brady SF, Singh S, Crouthamel MC, Holloway MK,
Coburn CA, Garsky VM, Bogusky M, Pennington MW,
Vacca JP, Hazuda D, Lai MT (2004) Rational design
and synthesis of selective BACE-1 inhibitors. Bioorg Med
Chem Lett 14, 601-604.
Coburn CA, Stachel SJ, Li YM, Rush DM, Steele TG,
Chen-Dodson E, Holloway MK, Xu M, Huang Q, Lai MT,
DiMuzio J, Crouthamel MC, Shi XP, Sardana V, Chen
Z, Munshi S, Kuo L, Makara GM, Annis DA, Tadikonda
PK, Nash HM, Vacca JP, Wang T (2004) Identification
of a small molecule nonpeptide active site beta-secretase
inhibitor that displays a nontraditional binding mode for
aspartyl proteases. J Med Chem 47, 6117-6119.
Coburn CA, Stachel SJ, Jones KG, Steele TG, Rush DM,
DiMuzio J, Pietrak BL, Lai MT, Huang Q, Lineberger J, Jin
L, Munshi S, Katharine HM, Espeseth A, Simon A, Hazuda
D, Graham SL, Vacca JP (2006) BACE-1 inhibition by a
series of psi [CH2NH] reduced amide isosteres. Bioorg
Med Chem Lett 16, 3635-3638.
Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel
MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi
S, Simon AJ, Kuo L, Vacca JP (2004) Structure-based
design of potent and selective cell-permeable inhibitors of
human beta-secretase (BACE-1). J Med Chem 47, 64476450.
Stachel SJ, Coburn CA, Steele TG, Crouthamel MC,
Pietrak BL, Lai MT, Holloway MK, Munshi SK, Graham SL, Vacca JP (2006) Conformationally biased P3
amide replacements of beta-secretase inhibitors. Bioorg
Med Chem Lett 16, 641-644.
Stachel SJ, Coburn CA, Sankaranarayanan S, Price EA,
Wu G, Crouthamel M, Pietrak BL, Huang Q, Lineberger
J, Espeseth AS, Jin L, Ellis J, Holloway MK, Munshi
S, Allison T, Hazuda D, Simon AJ, Graham SL, Vacca
JP (2006) Macrocyclic inhibitors of beta-secretase: Functional activity in an animal model. J Med Chem 49, 61476150.
Stachel SJ, Coburn CA, Rush D, Jones KL, Zhu H,
Rajapakse H, Graham SL, Simon A, Katharine HM, Allison TJ, Munshi SK, Espeseth AS, Zuck P, Colussi D,
Wolfe A, Pietrak BL, Lai MT, Vacca JP (2009) Discovery
of aminoheterocycles as a novel beta-secretase inhibitor
class: pH dependence on binding activity part 1. Bioorg
Med Chem Lett 19, 2977-2980.
Espeseth AS, Xu M, Huang Q, Coburn CA, Jones KL,
Ferrer M, Zuck PD, Strulovici B, Price EA, Wu G, Wolfe
AL, Lineberger JE, Sardana M, Tugusheva K, Pietrak BL,
Crouthamel MC, Lai MT, Dodson EC, Bazzo R, Shi XP,
Simon AJ, Li Y, Hazuda DJ (2005) Compounds that bind
APP and inhibit Abeta processing in vitro suggest a novel
approach to Alzheimer disease therapeutics. J Biol Chem
280, 17792-17797.
Rajapakse HA, Nantermet PG, Selnick HG, Munshi S,
McGaughey GB, Lindsley SR, Young MB, Lai MT, Espeseth AS, Shi XP, Colussi D, Pietrak B, Crouthamel MC,
Tugusheva K, Huang Q, Xu M, Simon AJ, Kuo L, Hazuda
DJ, Graham S, Vacca JP (2006) Discovery of oxadiazoyl
tertiary carbinamine inhibitors of beta-secretase (BACE1). J Med Chem 49, 7270-7273.
[603]
[604]
[605]
[606]
[607]
[608]
[609]
[610]
[611]
[612]
[613]
Rajapakse HA, Nantermet PG, Selnick HG, Barrow JC,
McGaughey GB, Munshi S, Lindsley SR, Young MB, Ngo
PL, Holloway MK, Lai MT, Espeseth AS, Shi XP, Colussi
D, Pietrak B, Crouthamel MC, Tugusheva K, Huang Q,
Xu M, Simon AJ, Kuo L, Hazuda DJ, Graham S, Vacca
JP (2010) SAR of tertiary carbinamine derived BACE1
inhibitors: Role of aspartate ligand amine pKa in enzyme
inhibition. Bioorg Med Chem Lett 20, 1885-1889.
Barrow JC, Rittle KE, Ngo PL, Selnick HG, Graham
SL, Pitzenberger SM, McGaughey GB, Colussi D, Lai
MT, Huang Q, Tugusheva K, Espeseth AS, Simon AJ,
Munshi SK, Vacca JP (2007) Design and synthesis of
2,3,5-substituted imidazolidin-4-one inhibitors of BACE1. ChemMedChem 2, 995-999.
Hills ID, Vacca JP (2007) Progress toward a practical
BACE-1 inhibitor. Curr Opin Drug Discov Devel 10, 383391.
Holloway KM, McGaughey GB, Coburn CA, Stachel SJ,
Jones KG, Stanton EL, Gregro AR, Lai MT, Crouthamel
MC, Pietrak BL, Munshi SK (2007) Evaluating scoring functions for docking and designing beta-secretase
inhibitors. Bioorg Med Chem Lett 17, 823-827.
Holloway KM, Hunt P, McGaughey GB (2009) Structure
and modeling in the design of ␤-and ␥-secretase inhibitors.
Drug Dev Res 70, 70-93.
Lindsley SR, Moore KP, Rajapakse HA, Selnick HG,
Young MB, Zhu H, Munshi S, Kuo L, McGaughey
GB, Colussi D, Crouthamel MC, Lai MT, Pietrak B,
Price EA, Sankaranarayanan S, Simon AJ, Seabrook GR,
Hazuda DJ, Pudvah NT, Hochman JH, Graham SL, Vacca
JP, Nantermet PG (2007) Design, synthesis, and SAR
of macrocyclic tertiary carbinamine BACE-1 inhibitors.
Bioorg Med Chem Lett 17, 4057-4061.
McGaughey GB, Colussi D, Graham SL, Lai MT, Munshi
SK, Nantermet PG, Pietrak B, Rajapakse HA, Selnick HG,
Stauffer SR, Holloway MK (2007) Beta-secretase (BACE1) inhibitors: Accounting for 10s loop flexibility using
rigid active sites. Bioorg Med Chem Lett 17, 1117-1121.
Moore KP, Zhu H, Rajapakse HA, McGaughey GB,
Colussi D, Price EA, Sankaranarayanan S, Simon AJ,
Pudvah NT, Hochman JH, Allison T, Munshi SK,
Graham SL, Vacca JP, Nantermet PG (2007) Strategies
toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem
Lett 17, 5831-5835.
Stauffer SR, Stanton MG, Gregro AR, Steinbeiser MA,
Shaffer JR, Nantermet PG, Barrow JC, Rittle KE,
Collusi D, Espeseth AS, Lai MT, Pietrak BL, Holloway
MK, McGaughey GB, Munshi SK, Hochman JH, Simon
AJ, Selnick HG, Graham SL, Vacca JP (2007) Discovery
and SAR of isonicotinamide BACE-1 inhibitors that bind
beta-secretase in a N-terminal 10s-loop down conformation. Bioorg Med Chem Lett 17, 1788-1792.
Sankaranarayanan S, Price EA, Wu G, Crouthamel MC,
Shi XP, Tugusheva K, Tyler KX, Kahana J, Ellis J, Jin L,
Steele T, Stachel S, Coburn C, Simon AJ (2008) In vivo
beta-secretase 1 inhibition leads to brain Abeta lowering
and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1. J Pharmacol
Exp Ther 324, 957-969.
Sankaranarayanan S, Holahan MA, Colussi D, Crouthamel
MC, Devanarayan V, Ellis J, Espeseth A, Gates AT, Graham SL, Gregro AR, Hazuda D, Hochman JH, Holloway
K, Jin L, Kahana J, Lai MT, Lineberger J, McGaughey G,
Moore KP, Nantermet P, Pietrak B, Price EA, Rajapakse
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[614]
[615]
[616]
[617]
[618]
[619]
[620]
[621]
[621]
H, Stauffer S, Steinbeiser MA, Seabrook G, Selnick HG,
Shi XP, Stanton MG, Swestock J, Tugusheva K, Tyler
KX, Vacca JP, Wong J, Wu G, Xu M, Cook JJ, Simon
AJ (2009) First demonstration of cerebrospinal fluid and
plasma A beta lowering with oral administration of a betasite amyloid precursor protein-cleaving enzyme 1 inhibitor
in nonhuman primates. J Pharmacol Exp Ther 328, 131140.
Hills ID, Holloway MK, de LP, Nomland A, Zhu H,
Rajapakse H, Allison TJ, Munshi SK, Colussi D, Pietrak
BL, Toolan D, Haugabook SJ, Graham SL, Stachel SJ
(2009) A conformational constraint improves a betasecretase inhibitor but for an unexpected reason. Bioorg
Med Chem Lett 19, 4993-4995.
Nantermet PG, Rajapakse HA, Stanton MG, Stauffer SR,
Barrow JC, Gregro AR, Moore KP, Steinbeiser MA,
Swestock J, Selnick HG, Graham SL, McGaughey GB,
Colussi D, Lai MT, Sankaranarayanan S, Simon AJ,
Munshi S, Cook JJ, Holahan MA, Michener MS, Vacca
JP (2009) Evolution of tertiary carbinamine BACE-1
inhibitors: Abeta reduction in rhesus CSF upon oral dosing. ChemMedChem 4, 37-40.
Steele TG, Hills ID, Nomland AA, de LP, Allison T,
McGaughey G, Colussi D, Tugusheva K, Haugabook SJ,
Espeseth AS, Zuck P, Graham SL, Stachel SJ (2009) Identification of a small molecule beta-secretase inhibitor that
binds without catalytic aspartate engagement. Bioorg Med
Chem Lett 19, 17-20.
Cumming J, Babu S, Huang Y, Carrol C, Chen X, Favreau
L, Greenlee W, Guo T, Kennedy M, Kuvelkar R, Le T, Li G,
McHugh N, Orth P, Ozgur L, Parker E, Saionz K, Stamford
A, Strickland C, Tadesse D, Voigt J, Zhang L, Zhang Q
(2010) Piperazine sulfonamide BACE1 inhibitors: Design,
synthesis, and in vivo characterization 4. Bioorg Med Chem
Lett 20, 2837-2842.
Zhu H, Young MB, Nantermet PG, Graham SL, Colussi D,
Lai MT, Pietrak B, Price EA, Sankaranarayanan S, Shi XP,
Tugusheva K, Holahan MA, Michener MS, Cook JJ, Simon
A, Hazuda DJ, Vacca JP, Rajapakse HA (2010) Rapid P1
SAR of brain penetrant tertiary carbinamine derived BACE
inhibitors. Bioorg Med Chem Lett 20, 1779-1782.
Wyss DF, Wang YS, Eaton HL, Strickland C, Voigt JH, Zhu
Z, Stamford AW (2012) Combining NMR and x-ray crystallography in fragment-based drug discovery: Discovery
of highly potent and selective BACE-1 inhibitors. Top Curr
Chem 317, 83-114.
Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ,
McGaughey G, Katharine HM, Allison T, Munshi S,
Zuck P, Colussi D, Tugasheva K, Wolfe A, Graham
SL, Vacca JP (2012) Discovery of pyrrolidine-based
beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding
efficiency. Bioorg Med Chem Lett 22, 240-244.
Gruninger-Leitch F, Schlatter D, Kung E, Nelbock P,
Dobeli H (2002) Substrate and inhibitor profile of BACE
(beta-secretase) and comparison with other mammalian
aspartic proteases. J Biol Chem 277, 4687-4693.
[2]Mandal M, Zhu Z, Cumming JN, Liu X, Strickland
C, Mazzola RD, Caldwell JP, Leach P, Grzelak M, Hyde
L, Zhang Q, Terracina G, Zhang L, Chen X, Kuvelkar
R, Kennedy ME, Favreau L, Cox K, Orth P, Buevich A,
Voigt JH, Wang H, Kazakevich I, McKittrick BA, Greenlee
W, Parker EM, Stamford AW (2012) Design and validation of bicyclic iminopyrimidinones as beta amyloid
cleaving enzyme-1 (BACE1) inhibitors - Conformational
[622]
[623]
[624]
[625]
[626]
[627]
[628]
[629]
[630]
617
constraint to favor a bioactive conformation. J Med Chem,
doi: 10.1021/jm301039cKuglstatter A, Stahl M, Peters JU, Huber W, Stihle M,
Schlatter D, Benz J, Ruf A, Roth D, Enderle T, Hennig
M (2008) Tyramine fragment binding to BACE-1. Bioorg
Med Chem Lett 18, 1304-1307.
Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT Jr, Hickman D, Hitchcock SA, Jordan B, Li V,
Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Powers TS, Rattan C, Sickmier EA, St JD Jr, Wahl RC, Wen
PH, Wood S (2011) From fragment screening to in vivo
efficacy: Optimization of a series of 2-aminoquinolines
as potent inhibitors of beta-site amyloid precursor protein
cleaving enzyme 1 (BACE1). J Med Chem 54, 5836-5857.
Dineen TA, Weiss MM, Williamson T, Acton P, BabuKhan S, Bartberger MD, Brown J, Chen K, Cheng Y,
Citron M, Croghan MD, Dunn RT, Esmay J, Graceffa RF,
Harried SD, Hickman D, Hitchcock SA, Horne DB, Huang
H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR,
La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen
TT, Pennington LD, San MT, Sickmier EA, Vargas HM,
Wahl RC, Wen PH, Whittington DA, Wood S, Xue Q, Yang
BH, Patel VF, Zhong W (2012) Design and synthesis of
potent, orally efficacious hydroxyethylamine derived betasite amyloid precursor protein cleaving enzyme (BACE1)
inhibitors. J Med Chem, doi: 10.1021/jm300118s [Epubl
ahead of print].
Weiss MM, Williamson T, Babu-Khan S, Bartberger MD,
Brown J, Chen K, Cheng Y, Citron M, Croghan MD,
Dineen TA, Esmay J, Graceffa RF, Harried S, Hickman
D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah
R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez
P, Louie S, Monenschein H, Nguyen TT, Pennington LD,
Rattan C, San MT, Sickmier EA, Wahl RC, Wen PH, Wood
S, Xue Q, Yang BH, Patel VF, Zhong W (2012) Design and
preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust
reduction of central beta-amyloid. J Med Chem, doi:
10.1021/jm300119p [Epubl ahead of print].
Congreve M, Aharony D, Albert J, Callaghan O,
Campbell J, Carr RA, Chessari G, Cowan S, Edwards
PD, Frederickson M, McMenamin R, Murray CW, Patel
S, Wallis N (2007) Application of fragment screening by
X-ray crystallography to the discovery of aminopyridines
as inhibitors of beta-secretase. J Med Chem 50, 1124-1132.
Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik
D, Callaghan O, Campbell JB, Carr RA, Chessari G,
Congreve M, Frederickson M, Folmer RH, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC,
Murray CW, Olsson LL, Patel S, Spear N, Tian G (2007)
Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors
with nanomolar potency, cellular activity, and high ligand
efficiency. J Med Chem 50, 5912-5925.
Geschwindner S, Olsson LL, Albert JS, Deinum J,
Edwards PD, de BT, Folmer RH (2007) Discovery of a
novel warhead against beta-secretase through fragmentbased lead generation. J Med Chem 50, 5903-5911.
Murray CW, Callaghan O, Chessari G, Cleasby A,
Congreve M, Frederickson M, Hartshorn MJ, McMenamin
R, Patel S, Wallis N (2007) Application of fragment screening by X-ray crystallography to beta-secretase. J Med
Chem 50, 1116-1123.
Kornacker MG, Lai Z, Witmer M, Ma J, Hendrick J, Lee
VG, Riexinger DJ, Mapelli C, Metzler W, Copeland RA
618
[631]
[632]
[633]
[634]
[635]
[636]
[637]
[638]
[639]
[640]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
(2005) An inhibitor binding pocket distinct from the catalytic active site on human beta-APP cleaving enzyme.
Biochemistry 44, 11567-11573.
Iben LG, Kopcho L, Marcinkeviciene J, Zheng C, Thompson LA, Albright CF, Toyn JH (2008) [3H]BMS-599240–a
novel tritiated ligand for the characterization of BACE1
inhibitors. Eur J Pharmacol 593, 10-15.
Wu YJ, Zhang Y, Good AC, Burton CR, Toyn JH, Albright
CF, Macor JE, Thompson LA (2009) Synthesis and
SAR of hydroxyethylamine based phenylcarboxyamides
as inhibitors of BACE. Bioorg Med Chem Lett 19, 26542660.
Marcin LR, Higgins MA, Zusi FC, Zhang Y, Dee
MF, Parker MF, Muckelbauer JK, Camac DM, Morin
PE, Ramamurthy V, Tebben AJ, Lentz KA, Grace JE,
Marcinkeviciene JA, Kopcho LM, Burton CR, Barten
DM, Toyn JH, Meredith JE, Albright CF, Bronson JJ,
Macor JE, Thompson LA (2011) Synthesis and SAR of
indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1. Bioorg Med Chem Lett 21,
537-541.
Thompson LA, Shi J, Decicco CP, Tebben AJ, Olson RE,
Boy KM, Guernon JM, Good AC, Liauw A, Zheng C,
Copeland RA, Combs AP, Trainor GL, Camac DM, Muckelbauer JK, Lentz KA, Grace JE, Burton CR, Toyn JH,
Barten DM, Marcinkeviciene J, Meredith JE, Albright CF,
Macor JE (2011) Synthesis and in vivo evaluation of cyclic
diaminopropane BACE-1 inhibitors. Bioorg Med Chem
Lett 21, 6909-6915.
Boy KM, Guernon JM, Shi J, Toyn JH, Meredith
JE, Barten DM, Burton CR, Albright CF, Marcinkeviciene J, Good AC, Tebben AJ, Muckelbauer JK, Camac
DM, Lentz KA, Bronson JJ, Olson RE, Macor JE,
Thompson LA (2011) Monosubstituted gamma-lactam
and conformationally constrained 1,3-diaminopropan-2ol transition-state isostere inhibitors of beta-secretase
(BACE). Bioorg Med Chem Lett 21, 6916-6924.
Tung JS, Davis DL, Anderson JP, Walker DE, Mamo
S, Jewett N, Hom RK, Sinha S, Thorsett ED, John V
(2002) Design of substrate-based inhibitors of human betasecretase. J Med Chem 45, 259-262.
Hom RK, Fang LY, Mamo S, Tung JS, Guinn AC, Walker
DE, Davis DL, Gailunas AF, Thorsett ED, Sinha S, Knops
JE, Jewett NE, Anderson JP, John V (2003) Design and
synthesis of statine-based cell-permeable peptidomimetic
inhibitors of human beta-secretase. J Med Chem 46, 17991802.
Hom RK, Gailunas AF, Mamo S, Fang LY, Tung JS, Walker
DE, Davis D, Thorsett ED, Jewett NE, Moon JB, John
V (2004) Design and synthesis of hydroxyethylene-based
peptidomimetic inhibitors of human beta-secretase. J Med
Chem 47, 158-164.
Maillard MC, Hom RK, Benson TE, Moon JB, Mamo
S, Bienkowski M, Tomasselli AG, Woods DD, Prince
DB, Paddock DJ, Emmons TL, Tucker JA, Dappen MS,
Brogley L, Thorsett ED, Jewett N, Sinha S, John V
(2007) Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors
of human beta-secretase. J Med Chem 50, 776-781.
Sealy JM, Truong AP, Tso L, Probst GD, Aquino J, Hom
RK, Jagodzinska BM, Dressen D, Wone DW, Brogley L,
John V, Tung JS, Pleiss MA, Tucker JA, Konradi AW, Dappen MS, Toth G, Pan H, Ruslim L, Miller J, Bova MP, Sinha
S, Quinn KP, Sauer JM (2009) Design and synthesis of
cell potent BACE-1 inhibitors: Structure-activity relation-
[641]
[642]
[643]
[644]
[645]
[646]
[647]
[648]
[649]
[650]
ship of P1 substituents. Bioorg Med Chem Lett 19, 63866391.
Probst GD, Bowers S, Sealy JM, Stupi B, Dressen D,
Jagodzinska BM, Aquino J, Gailunas A, Truong AP, Tso L,
Xu YZ, Hom RK, John V, Tung JS, Pleiss MA, Tucker JA,
Konradi AW, Sham HL, Jagodzinski J, Toth G, Brecht E,
Yao N, Pan H, Lin M, Artis DR, Ruslim L, Bova MP, Sinha
S, Yednock TA, Gauby S, Zmolek W, Quinn KP, Sauer JM
(2010) Design and synthesis of hydroxyethylamine (HEA)
BACE-1 inhibitors: Structure-activity relationship of the
aryl region. Bioorg Med Chem Lett 20, 6034-6039.
Truong AP, Probst GD, Aquino J, Fang L, Brogley L,
Sealy JM, Hom RK, Tucker JA, John V, Tung JS, Pleiss
MA, Konradi AW, Sham HL, Dappen MS, Toth G, Yao
N, Brecht E, Pan H, Artis DR, Ruslim L, Bova MP,
Sinha S, Yednock TA, Zmolek W, Quinn KP, Sauer JM
(2010) Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: Structure-activity relationship
of P2’ substituents. Bioorg Med Chem Lett 20, 4789-4794.
Truong AP, Toth G, Probst GD, Sealy JM, Bowers S, Wone
DW, Dressen D, Hom RK, Konradi AW, Sham HL, Wu J,
Peterson BT, Ruslim L, Bova MP, Kholodenko D, Motter RN, Bard F, Santiago P, Ni H, Chian D, Soriano F,
Cole T, Brigham EF, Wong K, Zmolek W, Goldbach E,
Samant B, Chen L, Zhang H, Nakamura DF, Quinn KP,
Yednock TA, Sauer JM (2010) Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in
a preclinical animal model. Bioorg Med Chem Lett 20,
6231-6236.
Tounge BA, Reynolds CH (2003) Calculation of the binding affinity of beta-secretase inhibitors using the linear
interaction energy method. J Med Chem 46, 2074-2082.
Rajamani R, Reynolds CH (2004) Modeling the protonation states of the catalytic aspartates in beta-secretase. J
Med Chem 47, 5159-5166.
Rajamani R, Reynolds CH (2004) Modeling the binding
affinities of beta-secretase inhibitors: Application to subsite specificity. Bioorg Med Chem Lett 14, 4843-4846.
Tounge BA, Rajamani R, Baxter EW, Reitz AB, Reynolds
CH (2006) Linear interaction energy models for betasecretase (BACE) inhibitors: Role of van der Waals,
electrostatic, and continuum-solvation terms. J Mol Graph
Model 24, 475-484.
Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken
MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott
MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ,
Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd
RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (2007)
2-Amino-3,4-dihydroquinazolines as inhibitors of BACE1 (beta-site APP cleaving enzyme): Use of structure based
design to convert a micromolar hit into a nanomolar lead.
J Med Chem 50, 4261-4264.
Huang Y, Strobel ED, Ho CY, Reynolds CH, Conway KA,
Piesvaux JA, Brenneman DE, Yohrling GJ, Moore AH,
Rosenthal D, Alexander RS, Tounge BA, Mercken M, Vandermeeren M, Parker MH, Reitz AB, Baxter EW (2010)
Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads. Bioorg Med Chem Lett 20,
3158-3160.
Shuto D, Kasai S, Kimura T, Liu P, Hidaka K, Hamada
T, Shibakawa S, Hayashi Y, Hattori C, Szabo B, Ishiura
S, Kiso Y (2003) KMI-008, a novel beta-secretase
inhibitor containing a hydroxymethylcarbonyl isostere as a
transition-state mimic: Design and synthesis of substratebased octapeptides. Bioorg Med Chem Lett 13, 4273-4276.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[651]
[652]
[653]
[654]
[655]
[656]
[657]
[658]
[659]
[660]
[661]
[662]
[663]
Kimura T, Shuto D, Kasai S, Liu P, Hidaka K, Hamada
T, Hayashi Y, Hattori C, Asai M, Kitazume S, Saido
TC, Ishiura S, Kiso Y (2004) KMI-358 and KMI-370,
highly potent and small-sized BACE1 inhibitors containing phenylnorstatine. Bioorg Med Chem Lett 14,
1527-1531.
Kimura T, Shuto D, Hamada Y, Igawa N, Kasai S, Liu
P, Hidaka K, Hamada T, Hayashi Y, Kiso Y (2005)
Design and synthesis of highly active Alzheimer’s betasecretase (BACE1) inhibitors, KMI-420 and KMI-429,
with enhanced chemical stability. Bioorg Med Chem Lett
15, 211-215.
Kimura T, Hamada Y, Stochaj M, Ikari H, Nagamine
A, Abdel-Rahman H, Igawa N, Hidaka K, Nguyen JT,
Saito K, Hayashi Y, Kiso Y (2006) Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1
carboxylic acid bioisosteres. Bioorg Med Chem Lett 16,
2380-2386.
Hamada Y, Igawa N, Ikari H, Ziora Z, Nguyen JT, Yamani
A, Hidaka K, Kimura T, Saito K, Hayashi Y, Ebina M,
Ishiura S, Kiso Y (2006) beta-Secretase inhibitors: Modification at the P4 position and improvement of inhibitory
activity in cultured cells. Bioorg Med Chem Lett 16, 43544359.
Hamada Y, Ohta H, Miyamoto N, Yamaguchi R, Yamani
A, Hidaka K, Kimura T, Saito K, Hayashi Y, Ishiura S,
Kiso Y (2008) Novel non-peptidic and small-sized BACE1
inhibitors. Bioorg Med Chem Lett 18, 1643-1647.
Hamada Y, Abdel-Rahman H, Yamani A, Nguyen JT,
Stochaj M, Hidaka K, Kimura T, Hayashi Y, Saito K,
Ishiura S, Kiso Y (2008) BACE1 inhibitors: Optimization by replacing the P1 residue with non-acidic moiety.
Bioorg Med Chem Lett 18, 1649-1653.
Hamada Y, Ohta H, Miyamoto N, Sarma D, Hamada T,
Nakanishi T, Yamasaki M, Yamani A, Ishiura S, Kiso
Y (2009) Significance of interactions of BACE1-Arg235
with its ligands and design of BACE1 inhibitors with P2
pyridine scaffold. Bioorg Med Chem Lett 19, 2435-2439.
Hamada Y, Tagad HD, Nishimura Y, Ishiura S, Kiso Y
(2011) Tripeptidic BACE1 inhibitors devised by in-silico
conformational structure-based design. Bioorg Med Chem
Lett 22, 1130-1135.
Ziora Z, Kimura T, Kiso Y (2006) Small-sized BACE1
inhibitors. Drugs Future 31, 53-63.
Ziora Z, Kasai S, Hidaka K, Nagamine A, Kimura T,
Hayashi Y, Kiso Y (2007) Design and synthesis of
BACE1 inhibitors containing a novel norstatine derivative
(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid.
Bioorg Med Chem Lett 17, 1629-1633.
Kakizawa T, Hidaka K, Hamada D, Yamaguchi R, Uemura
T, Kitamura H, Tagad HD, Hamada T, Ziora Z, Hamada
Y, Kimura T, Kiso Y (2010) Tetrapeptides, as small-sized
peptidic inhibitors; synthesis and their inhibitory activity
against BACE1. J Pept Sci 16, 257-262.
Tagad HD, Hamada Y, Nguyen JT, Hamada T, bdelRahman H, Yamani A, Nagamine A, Ikari H, Igawa N,
Hidaka K, Sohma Y, Kimura T, Kiso Y (2010) Design
of pentapeptidic BACE1 inhibitors with carboxylic acid
bioisosteres at P1’ and P4 positions. Bioorg Med Chem
18, 3175-3186.
Tagad HD, Hamada Y, Nguyen JT, Hidaka K,
Hamada T, Sohma Y, Kimura T, Kiso Y (2011)
Structure-guided design and synthesis of P1 position
1-phenylcycloalkylamine-derived pentapeptidic BACE1
inhibitors. Bioorg Med Chem 19, 5238-5246.
[664]
[665]
[666]
[667]
[668]
[669]
[670]
[671]
[672]
[673]
[674]
[675]
619
Ebina M, Futai E, Tanabe C, Sasagawa N, Kiso Y, Ishiura
S (2009) Inhibition by KMI-574 leads to dislocalization of BACE1 from lipid rafts. J Neurosci Res 87, 360368.
Asai M, Hattori C, Iwata N, Saido TC, Sasagawa N,
Szabo B, Hashimoto Y, Maruyama K, Tanuma S, Kiso Y,
Ishiura S (2006) The novel beta-secretase inhibitor KMI429 reduces amyloid beta peptide production in amyloid
precursor protein transgenic and wild-type mice. J Neurochem 96, 533-540.
Lu Q, Chen WY, Zhu ZY, Chen J, Xu YC, Kaewpet M,
Rukachaisirikul V, Chen LL, Shen X (2012) L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases
beta-amyloid peptide production in HEK293-APPswe
cells. Acta Pharmacol Sin, doi: 10.1038/aps.2012.74
[Epubl ahead of print].
Machauer R, Veenstra S, Rondeau JM, Tintelnot-Blomley
M, Betschart C, Neumann U, Paganetti P (2009) Structurebased design and synthesis of macrocyclic peptidomimetic
beta-secretase (BACE-1) inhibitors. Bioorg Med Chem
Lett 19, 1361-1365.
Machauer R, Laumen K, Veenstra S, Rondeau JM,
Tintelnot-Blomley M, Betschart C, Jaton AL, Desrayaud
S, Staufenbiel M, Rabe S, Paganetti P, Neumann U (2009)
Macrocyclic peptidomimetic beta-secretase (BACE-1)
inhibitors with activity in vivo. Bioorg Med Chem Lett 19,
1366-1370.
Lerchner A, Machauer R, Betschart C, Veenstra S, Rueeger
H, McCarthy C, Tintelnot-Blomley M, Jaton AL, Rabe S,
Desrayaud S, Enz A, Staufenbiel M, Paganetti P, Rondeau
JM, Neumann U (2010) Macrocyclic BACE-1 inhibitors
acutely reduce Abeta in brain after po application. Bioorg
Med Chem Lett 20, 603-607.
Rueeger H, Rondeau JM, McCarthy C, Mobitz H,
Tintelnot-Blomley M, Neumann U, Desrayaud S (2011)
Structure based design, synthesis and SAR of cyclic
hydroxyethylamine (HEA) BACE-1 inhibitors. Bioorg
Med Chem Lett 21, 1942-1947.
Rueeger H, Lueoend R, Rogel O, Rondeau JM, Mobitz
H, Machauer R, Jacobson L, Staufenbiel M, Desrayaud
S, Neumann U (2012) Discovery of cyclic sulfone
hydroxyethylamines as potent and selective beta-site APPcleaving enzyme 1 (BACE1) Inhibitors: Structure-based
design and in vivo reduction of amyloid beta-peptides. J
Med Chem 55, 3364-3386.
Hu B, Fan KY, Bridges K, Chopra R, Lovering F, Cole
D, Zhou P, Ellingboe J, Jin G, Cowling R, Bard J (2004)
Synthesis and SAR of bis-statine based peptides as BACE
1 inhibitors. Bioorg Med Chem Lett 14, 3457-3460.
Bridges KG, Chopra R, Lin L, Svenson K, Tam A, Jin
G, Cowling R, Lovering F, Akopian TN, Blasio-Smith
E, Annis-Freeman B, Marvell TH, LaVallie ER, Zollner
RS, Bard J, Somers WS, Stahl ML, Kriz RW (2006) A
novel approach to identifying beta-secretase inhibitors:
Bis-statine peptide mimetics discovered using structure
and spot synthesis. Peptides 27, 1877-1885.
Cole DC, Manas ES, Stock JR, Condon JS, Jennings LD,
Aulabaugh A, Chopra R, Cowling R, Ellingboe JW, Fan
KY, Harrison BL, Hu Y, Jacobsen S, Jin G, Lin L, Lovering FE, Malamas MS, Stahl ML, Strand J, Sukhdeo MN,
Svenson K, Turner MJ, Wagner E, Wu J, Zhou P, Bard J
(2006) Acylguanidines as small-molecule beta-secretase
inhibitors. J Med Chem 49, 6158-6161.
Cole DC, Stock JR, Chopra R, Cowling R, Ellingboe JW,
Fan KY, Harrison BL, Hu Y, Jacobsen S, Jennings LD,
620
[676]
[677]
[678]
[679]
[680]
[681]
[682]
[683]
[684]
[685]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Jin G, Lohse PA, Malamas MS, Manas ES, Moore WJ,
O’Donnell MM, Olland AM, Robichaud AJ, Svenson K,
Wu J, Wagner E, Bard J (2008) Acylguanidine inhibitors
of beta-secretase: Optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding
pockets. Bioorg Med Chem Lett 18, 1063-1066.
Fobare WF, Solvibile WR, Robichaud AJ, Malamas MS,
Manas E, Turner J, Hu Y, Wagner E, Chopra R, Cowling R,
Jin G, Bard J (2007) Thiophene substituted acylguanidines
as BACE1 inhibitors. Bioorg Med Chem Lett 17, 53535356.
Freskos JN, Fobian YM, Benson TE, Bienkowski MJ,
Brown DL, Emmons TL, Heintz R, Laborde A, McDonald JJ, Mischke BV, Molyneaux JM, Moon JB, Mullins
PB, Bryan PD, Paddock DJ, Tomasselli AG, Winterrowd
G (2007) Design of potent inhibitors of human betasecretase. Part 1. Bioorg Med Chem Lett 17, 73-77.
Freskos JN, Fobian YM, Benson TE, Moon JB,
Bienkowski MJ, Brown DL, Emmons TL, Heintz R,
Laborde A, McDonald JJ, Mischke BV, Molyneaux JM,
Mullins PB, Bryan PD, Paddock DJ, Tomasselli AG,
Winterrowd G (2007) Design of potent inhibitors of
human beta-secretase. Part 2. Bioorg Med Chem Lett 17,
78-81.
Kortum SW, Benson TE, Bienkowski MJ, Emmons
TL, Prince DB, Paddock DJ, Tomasselli AG, Moon
JB, Laborde A, TenBrink RE (2007) Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of
BACE1. Bioorg Med Chem Lett 17, 3378-3383.
Jennings LD, Cole DC, Stock JR, Sukhdeo MN, Ellingboe
JW, Cowling R, Jin G, Manas ES, Fan KY, Malamas MS,
Harrison BL, Jacobsen S, Chopra R, Lohse PA, Moore
WJ, O’Donnell MM, Hu Y, Robichaud AJ, Turner MJ,
Wagner E, Bard J (2008) Acylguanidine inhibitors of betasecretase: Optimization of the pyrrole ring substituents
extending into the S1 substrate binding pocket. Bioorg
Med Chem Lett 18, 767-771.
Malamas MS, Erdei J, Gunawan I, Barnes K, Johnson M,
Hui Y, Turner J, Hu Y, Wagner E, Fan K, Olland A, Bard
J, Robichaud AJ (2009) Aminoimidazoles as potent and
selective human beta-secretase (BACE1) inhibitors. J Med
Chem 52, 6314-6323.
Malamas MS, Erdei J, Gunawan I, Turner J, Hu Y, Wagner
E, Fan K, Chopra R, Olland A, Bard J, Jacobsen S, Magolda
RL, Pangalos M, Robichaud AJ (2010) Design and synthesis of 5,5 -disubstituted aminohydantoins as potent and
selective human beta-secretase (BACE1) inhibitors. J Med
Chem 53, 1146-1158.
Malamas MS, Barnes K, Johnson M, Hui Y, Zhou P, Turner
J, Hu Y, Wagner E, Fan K, Chopra R, Olland A, Bard J, Pangalos M, Reinhart P, Robichaud AJ (2010) Di-substituted
pyridinyl aminohydantoins as potent and highly selective
human beta-secretase (BACE1) inhibitors. Bioorg Med
Chem 18, 630-639.
Malamas MS, Barnes K, Hui Y, Johnson M, Lovering
F, Condon J, Fobare W, Solvibile W, Turner J, Hu Y,
Manas ES, Fan K, Olland A, Chopra R, Bard J, Pangalos MN, Reinhart P, Robichaud AJ (2010) Novel pyrrolyl
2-aminopyridines as potent and selective human betasecretase (BACE1) inhibitors. Bioorg Med Chem Lett 20,
2068-2073.
Malamas MS, Robichaud A, Erdei J, Quagliato D, Solvibile W, Zhou P, Morris K, Turner J, Wagner E, Fan K,
Olland A, Jacobsen S, Reinhart P, Riddell D, Pangalos M
(2010) Design and synthesis of aminohydantoins as potent
[686]
[687]
[688]
[689]
[690]
[691]
[692]
[693]
[694]
[695]
[696]
[697]
and selective human beta-secretase (BACE1) inhibitors
with enhanced brain permeability. Bioorg Med Chem Lett
20, 6597-6605.
Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, Johnson M, Robichaud A, Zhou P, Yan Y, Solvibile W, Turner
J, Fan KY, Chopra R, Bard J, Pangalos MN (2011) New
pyrazolyl and thienyl aminohydantoins as potent BACE1
inhibitors: Exploring the S2 region. Bioorg Med Chem
Lett 21, 5164-5170.
Nowak P, Cole DC, Aulabaugh A, Bard J, Chopra R, Cowling R, Fan KY, Hu B, Jacobsen S, Jani M, Jin G, Lo
MC, Malamas MS, Manas ES, Narasimhan R, Reinhart
P, Robichaud AJ, Stock JR, Subrath J, Svenson K, Turner
J, Wagner E, Zhou P, Ellingboe JW (2010) Discovery and
initial optimization of 5,5 -disubstituted aminohydantoins
as potent beta-secretase (BACE1) inhibitors. Bioorg Med
Chem Lett 20, 632-635.
Zhou P, Li Y, Fan Y, Wang Z, Chopra R, Olland A, Hu Y,
Magolda RL, Pangalos M, Reinhart PH, Turner MJ, Bard
J, Malamas MS, Robichaud AJ (2010) Pyridinyl aminohydantoins as small molecule BACE1 inhibitors. Bioorg
Med Chem Lett 20, 2326-2329.
Efremov IV, Vajdos FF, Borzilleri K, Capetta S, Dorff PH,
Dutra JK, Mansour M, Chen H, Goldstein SW, Noell S,
Oborski CE, O’Connell TN, O’Sullivan TJ, Pandit J, Wang
H, Wei B, Withka JM, McColl A (2012) Discovery and
optimization of a novel spiro-pyrrolidine inhibitors of betasecretase (BACE1) through fragment based drug design.
J Med Chem, doi: 10.1021/jm201715d [Epubl ahead of
print].
Monenschein H, Horne DB, Bartberger MD, Hitchcock
SA, Nguyen TT, Patel VF, Pennington LD, Zhong W
(2012) Structure guided P1 modifications of HEA derived
beta-secretase inhibitors for the treatment of Alzheimer’s
disease. Bioorg Med Chem Lett 22, 3607-3611.
Godemann R, Madden J, Kramer J, Smith M, Fritz U,
Hesterkamp T, Barker J, Hoppner S, Hallett D, Cesura A,
Ebneth A, Kemp J (2009) Fragment-based discovery of
BACE1 inhibitors using functional assays. Biochemistry
48, 10743-10751.
Madden J, Dod JR, Godemann R, Kraemer J, Smith
M, Biniszkiewicz M, Hallett DJ, Barker J, Dyekjaer JD,
Hesterkamp T (2010) Fragment-based discovery and optimization of BACE1 inhibitors. Bioorg Med Chem Lett 20,
5329-5333.
Park H, Min K, Kwak HS, Koo KD, Lim D, Seo SW, Choi
JU, Platt B, Choi DY (2008) Synthesis, SAR, and X-ray
structure of human BACE-1 inhibitors with cyclic urea
derivatives. Bioorg Med Chem Lett 18, 2900-2904.
Manzenrieder F, Frank AO, Huber T, Dorner-Ciossek C,
Kessler H (2007) Synthesis and biological evaluation of
phosphino dipeptide isostere inhibitor of human betasecretase (BACE1). Bioorg Med Chem 15, 4136-4143.
Huber T, Manzenrieder F, Kuttruff CA, Dorner-Ciossek
C, Kessler H (2009) Prolonged stability by cyclization:
Macrocyclic phosphino dipeptide isostere inhibitors of
beta-secretase (BACE1). Bioorg Med Chem Lett 19, 44274431.
Huang W, Lv D, Yu H, Sheng R, Kim SC, Wu P, Luo K,
Li J, Hu Y (2010) Dual-target-directed 1,3-diphenylurea
derivatives: BACE 1 inhibitor and metal chelator against
Alzheimer’s disease. Bioorg Med Chem 18, 5610-5615.
Rajendran L, Schneider A, Schlechtingen G, Weidlich S,
Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder
C, Simons M, Jennings G, Knolker HJ, Simons K (2008)
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[698]
[699]
[700]
[701]
[702]
[703]
[704]
[705]
[706]
[707]
[708]
[709]
[710]
[711]
[712]
[713]
Efficient inhibition of the Alzheimer’s disease betasecretase by membrane targeting. Science 320, 520-523.
Arbel M, Yacoby I, Solomon B (2005) Inhibition of
amyloid precursor protein processing by beta-secretase
through site-directed antibodies. Proc Natl Acad Sci U S A
102, 7718-7723.
Boddapati S, Levites Y, Sierks MR (2011) Inhibiting betasecretase activity in Alzheimer’s disease cell models with
single-chain antibodies specifically targeting APP. J Mol
Biol 405, 436-447.
Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ,
Liu Y, Heise CE, Hoyte K, Luk W, Lu Y, Peng K, Wu P,
Rouge L, Zhang Y, Lazarus RA, Scearce-Levie K, Wang
W, Wu Y, Tessier-Lavigne M, Watts RJ (2011) A therapeutic antibody targeting BACE1 inhibits amyloid-beta
production in vivo. Sci Transl Med 3, 84ra43.
Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal
J, Elliott JM, Prabhu S, Watts RJ, Dennis MS (2011) Boosting brain uptake of a therapeutic antibody by reducing its
affinity for a transcytosis target. Sci Transl Med 3, 84ra44.
Boado RJ, Zhang Y, Wang Y, Pardridge WM (2009) Engineering and expression of a chimeric transferrin receptor
monoclonal antibody for blood-brain barrier delivery in
the mouse. Biotechnol Bioeng 102, 1251-1258.
Boado RJ, Zhou QH, Lu JZ, Hui EK, Pardridge WM (2010)
Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse
transferrin receptor. Mol Pharm 7, 237-244.
Zhou QH, Fu A, Boado RJ, Hui EK, Lu JZ, Pardridge
WM (2011) Receptor-mediated abeta amyloid antibody
targeting to Alzheimer’s disease mouse brain. Mol Pharm
8, 280-285.
Zhou QH, Boado RJ, Hui EK, Lu JZ, Pardridge WM (2011)
Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion
protein. Drug Metab Dispos 39, 1149-1154.
Zhou QH, Boado RJ, Pardridge WM (2012) Selective
plasma pharmacokinetics and brain uptake in the mouse
of enzyme fusion proteins derived from species-specific
receptor-targeted antibodies. J Drug Target 20, 715-719.
Pardridge WM, Boado RJ (2012) Reengineering biopharmaceuticals for targeted delivery across the blood-brain
barrier. Methods Enzymol 503, 269-292.
Boado RJ, Pardridge WM (2011) The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the
Blood-Brain Barrier. J Drug Deliv 2011, 296151.
Jiaranaikulwanitch J, Boonyarat C, Fokin VV, Vajragupta
O (2010) Triazolyl tryptoline derivatives as beta-secretase
inhibitors. Bioorg Med Chem Lett 20, 6572-6576.
Jiaranaikulwanitch J, Govitrapong P, Fokin VV, Vajragupta
O (2012) From BACE1 inhibitor to multifunctionality of tryptoline and tryptamine triazole derivatives for
Alzheimer’s disease. Molecules 17, 8312-8333.
Larbig G, Schmidt B (2006) Synthesis of tetramic and
tetronic acids as beta-secretase inhibitors. J Comb Chem
8, 480-490.
Linning P, Haussmann U, Beyer I, Weidlich S, Schieb H,
Wiltfang J, Klafki HW, Knolker HJ (2012) Optimisation
of BACE1 inhibition of tripartite structures by modification of membrane anchors, spacers and pharmacophores
- development of potential agents for the treatment
of Alzheimer’s disease. Org Biomol Chem 10, 82168235.
Schieb H, Weidlich S, Schlechtingen G, Linning P, Jennings G, Gruner M, Wiltfang J, Klafki HW, Knolker
[714]
[715]
[716]
[717]
[718]
[719]
[720]
[721]
[722]
[723]
[724]
[725]
[726]
621
HJ (2010) Structural design, solid-phase synthesis and
activity of membrane-anchored beta-secretase inhibitors
on Abeta generation from wild-type and Swedish-mutant
APP. Chemistry 16, 14412-14423.
Choi SJ, Cho JH, Im I, Lee SD, Jang JY, Oh YM, Jung
YK, Jeon ES, Kim YC (2010) Design and synthesis of
1,4-dihydropyridine derivatives as BACE-1 inhibitors. Eur
J Med Chem 45, 2578-2590.
Back M, Nyhlen J, Kvarnstrom I, Appelgren S, Borkakoti
N, Jansson K, Lindberg J, Nystrom S, Hallberg A, Rosenquist S, Samuelsson B (2008) Design, synthesis and SAR
of potent statine-based BACE-1 inhibitors: Exploration of
P1 phenoxy and benzyloxy residues. Bioorg Med Chem
16, 9471-9486.
Patey SJ, Edwards EA, Yates EA, Turnbull JE (2006) Heparin derivatives as inhibitors of BACE-1, the Alzheimer’s
beta-secretase, with reduced activity against factor Xa and
other proteases. J Med Chem 49, 6129-6132.
Patey SJ, Edwards EA, Yates EA, Turnbull JE (2008)
Engineered heparins: Novel beta-secretase inhibitors as
potential Alzheimer’s disease therapeutics. Neurodegener
Dis 5, 197-199.
Laras Y, Garino C, Dessolin J, Weck C, Moret V, Rolland A, Kraus JL (2009) New N(4)-substituted piperazine
naphthamide derivatives as BACE-1 inhibitors. J Enzyme
Inhib Med Chem 24, 181-187.
Barazza A, Gotz M, Cadamuro SA, Goettig P, Willem M,
Steuber H, Kohler T, Jestel A, Reinemer P, Renner C, Bode
W, Moroder L (2007) Macrocyclic statine-based inhibitors
of BACE-1. Chembiochem 8, 2078-2091.
Hanessian S, Yun H, Hou Y, Yang G, Bayrakdarian
M, Therrien E, Moitessier N, Roggo S, Veenstra S,
Tintelnot-Blomley M, Rondeau JM, Ostermeier C, Strauss
A, Ramage P, Paganetti P, Neumann U, Betschart C
(2005) Structure-based design, synthesis, and memapsin 2
(BACE) inhibitory activity of carbocyclic and heterocyclic
peptidomimetics. J Med Chem 48, 5175-5190.
Hanessian S, Yang G, Rondeau JM, Neumann U,
Betschart C, Tintelnot-Blomley M (2006) Structure-based
design and synthesis of macroheterocyclic peptidomimetic
inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE). J Med Chem 49,
4544-4567.
Hanessian S, Shao Z, Betschart C, Rondeau JM, Neumann
U, Tintelnot-Blomley M (2010) Structure-based design
and synthesis of novel P2/P3 modified, non-peptidic betasecretase (BACE-1) inhibitors. Bioorg Med Chem Lett 20,
1924-1927.
Niu Y, Wang Y, Zou X, Yang X, Ma C, Lu Y, Zhou B, Yuan
Y, Du G, Xu P (2010) Synthesis and preliminary evaluation
of peptidomimetic inhibitors of human beta-secretase. Eur
J Med Chem 45, 2089-2094.
Asso V, Ghilardi E, Bertini S, Digiacomo M, Granchi C,
Minutolo F, Rapposelli S, Bortolato A, Moro S, Macchia
M (2008) alpha-Naphthylaminopropan-2-ol Derivatives as
BACE1 Inhibitors. ChemMedChem 3, 1530-1534.
Bertini S, Ghilardi E, Asso V, Granchi C, Minutolo F,
Pineschi M, Di B, V, Bortolato A, Moro S, Saba A, Macchia
M (2010) BACE1 inhibitory activities of enantiomerically
pure, variously substituted N-(3-(4-benzhydrylpiperazin1-yl)-2-hydroxypropyl) arylsulfonamides. Bioorg Med
Chem 18, 7991-7996.
Bertini S, Asso V, Ghilardi E, Granchi C, Manera C, Minutolo F, Saccomanni G, Bortolato A, Mason J, Moro S,
Macchia M (2011) Carbazole-containing arylcarboxam-
622
[727]
[728]
[729]
[730]
[731]
[732]
[733]
[734]
[735]
[736]
[737]
[738]
[739]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
ides as BACE1 inhibitors. Bioorg Med Chem Lett 21,
6657-6661.
Ghosh AK, Devasamudram T, Hong L, DeZutter C, Xu
X, Weerasena V, Koelsch G, Bilcer G, Tang J (2005)
Structure-based design of cycloamide-urethane-derived
novel inhibitors of human brain memapsin 2 (betasecretase). Bioorg Med Chem Lett 15, 15-20.
Ghosh AK, Kumaragurubaran N, Hong L, Lei H, Hussain KA, Liu CF, Devasamudram T, Weerasena V, Turner
R, Koelsch G, Bilcer G, Tang J (2006) Design, synthesis
and X-ray structure of protein-ligand complexes: Important insight into selectivity of memapsin 2 (beta-secretase)
inhibitors. J Am Chem Soc 128, 5310-5311.
La Regina G, Piscitelli F, Silvestri R (2009) Synthetic
strategies of nonpeptidic b-secretase (BACE1) inhibitors.
J Heterocyclic Chem 46, 10-17.
Xiao K, Li X, Li J, Ma L, Hu B, Yu H, Fu Y, Wang R, Ma
Z, Qiu B, Li J, Hu D, Wang X, Shen J (2006) Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based
non-peptide beta-secretase (BACE) inhibitors. Bioorg Med
Chem 14, 4535-4551.
Zhu YP, Xiao K, Yu HP, Ma LP, Xiong B, Zhang HY,
Wang X, Li JY, Li J, Shen JK (2009) Discovery of
potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids. Acta Pharmacol
Sin 30, 259-269.
Sasaki H, Miki K, Kinoshita K, Koyama K, Juliawaty LD,
Achmad SA, Hakim EH, Kaneda M, Takahashi K (2010)
beta-Secretase (BACE-1) inhibitory effect of biflavonoids.
Bioorg Med Chem Lett 20, 4558-4560.
Bjorklund C, Adolfsson H, Jansson K, Lindberg J, Vrang
L, Hallberg A, Rosenquist S, Samuelsson B (2010) Discovery of potent BACE-1 inhibitors containing a new
hydroxyethylene (HE) scaffold: Exploration of P1 alkoxy
residues and an aminoethylene (AE) central core. Bioorg
Med Chem 18, 1711-1723.
Bjorklund C, Oscarson S, Benkestock K, Borkakoti N,
Jansson K, Lindberg J, Vrang L, Hallberg A, Rosenquist A,
Samuelsson B (2010) Design and synthesis of potent and
selective BACE-1 inhibitors. J Med Chem 53, 1458-1464.
Meredith JA, Bjorklund C, Adolfsson H, Jansson K, Hallberg A, Rosenquist A, Samuelsson B (2010) P2 -truncated
BACE-1 inhibitors with a novel hydroxethylene-like core.
Eur J Med Chem 45, 542-554.
Kumar AB, Anderson JM, Melendez AL, Manetsch R
(2012) Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors.
Bioorg Med Chem Lett 22, 4740-4744.
Chiriano G, De SA, Mancini F, Perez DI, Cavalli A,
Bolognesi ML, Legname G, Martinez A, Andrisano V,
Carloni P, Roberti M (2012) A small chemical library
of 2-aminoimidazole derivatives as BACE-1 inhibitors:
Structure-based design, synthesis, and biological evaluation. Eur J Med Chem 48, 206-213.
Andrau D, Dumanchin-Njock C, Ayral E, Vizzavona J,
Farzan M, Boisbrun M, Fulcrand P, Hernandez JF, Martinez J, Lefranc-Jullien S, Checler F (2003) BACE1- and
BACE2-expressing human cells: Characterization of betaamyloid precursor protein-derived catabolites, design of a
novel fluorimetric assay, and identification of new in vitro
inhibitors. J Biol Chem 278, 25859-25866.
Lefranc-Jullien S, Lisowski V, Hernandez JF, Martinez J,
Checler F (2005) Design and characterization of a new
cell-permeant inhibitor of the beta-secretase BACE1. Br J
Pharmacol 145, 228-235.
[740]
[741]
[742]
[743]
[744]
[745]
[746]
[747]
[748]
[749]
[750]
[751]
[752]
[753]
[754]
[755]
Russo F, Wangsell F, Sävmarker J, Jacobsson M, Larhed M
(2009) Synthesis and evaluation of a new class of tertiary
alcohol based BACE-1 inhibitors. Tetrahedron 65, 1004710059.
Wangsell F, Russo F, Savmarker J, Rosenquist A, Samuelsson B, Larhed M (2009) Design and synthesis of BACE-1
inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic. Bioorg Med Chem Lett 19, 4711-4714.
Wangsell F, Gustafsson K, Kvarnstrom I, Borkakoti N,
Edlund M, Jansson K, Lindberg J, Hallberg A, Rosenquist A, Samuelsson B (2010) Synthesis of potent BACE-1
inhibitors incorporating a hydroxyethylene isostere as central core. Eur J Med Chem 45, 870-882.
Wangsell F, Nordeman P, Savmarker J, Emanuelsson R,
Jansson K, Lindberg J, Rosenquist S, Samuelsson B,
Larhed M (2011) Investigation of alpha-phenylnorstatine
and alpha-benzylnorstatine as transition state isostere
motifs in the search for new BACE-1 inhibitors. Bioorg
Med Chem 19, 145-155.
Marcinkeviciene J, Luo Y, Graciani NR, Combs AP,
Copeland RA (2001) Mechanism of inhibition of beta-site
amyloid precursor protein-cleaving enzyme (BACE) by a
statine-based peptide. J Biol Chem 276, 23790-23794.
Xiong B, Huang XQ, Shen LL, Shen JH, Luo XM, Shen X,
Jiang HL, Chen KX (2004) Conformational flexibility of
beta-secretase: Molecular dynamics simulation and essential dynamics analysis. Acta Pharmacol Sin 25, 705-713.
Huang D, Luthi U, Kolb P, Edler K, Cecchini M, Audetat
S, Barberis A, Caflisch A (2005) Discovery of cellpermeable non-peptide inhibitors of beta-secretase by
high-throughput docking and continuum electrostatics calculations. J Med Chem 48, 5108-5111.
Polgar T, Keseru GM (2005) Virtual screening for betasecretase (BACE1) inhibitors reveals the importance of
protonation states at Asp32 and Asp228. J Med Chem 48,
3749-3755.
Huang D, Luthi U, Kolb P, Cecchini M, Barberis A,
Caflisch A (2006) In silico discovery of beta-secretase
inhibitors. J Am Chem Soc 128, 5436-5443.
Moitessier N, Therrien E, Hanessian S (2006) A method
for induced-fit docking, scoring, and ranking of flexible
ligands. Application to peptidic and pseudopeptidic betasecretase (BACE 1) inhibitors. J Med Chem 49, 58855894.
Polgar T, Keseru GM (2006) Ensemble docking into flexible active sites. Critical evaluation of FlexE against JNK-3
and beta-secretase. J Chem Inf Model 46, 1795-1805.
Yu N, Hayik SA, Wang B, Liao N, Reynolds CH, Merz
KM Jr (2006) Assigning the protonation states of the key
aspartates in beta-Secretase using QM/MM X-ray structure refinement. J Chem Theory Comput 2, 1057-1069.
English NJ (2007) Calculation of binding affinities of
HIV-1 RT and beta-secretase inhibitors using the linear
interaction energy method with explicit and continuum
solvation approaches. J Mol Model 13, 1081-1097.
Limongelli V, Marinelli L, Cosconati S, Braun HA,
Schmidt B, Novellino E (2007) Ensemble-docking
approach on BACE-1: Pharmacophore perception and
guidelines for drug design. ChemMedChem 2, 667-678.
Villaverde MC, Gonzalez-Louro L, Sussman F (2007) The
search for drug leads targeted to the beta-secretase: An
example of the roles of computer assisted approaches in
drug discovery. Curr Top Med Chem 7, 980-990.
Fujimoto T, Matsushita Y, Gouda H, Yamaotsu N, Hirono S
(2008) In silico multi-filter screening approaches for devel-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[756]
[757]
[758]
[759]
[760]
[761]
[762]
[763]
[764]
[765]
[766]
[767]
[768]
[769]
oping novel beta-secretase inhibitors. Bioorg Med Chem
Lett 18, 2771-2775.
Huang W, Yu H, Sheng R, Li J, Hu Y (2008)
Identification of pharmacophore model, synthesis and
biological evaluation of N-phenyl-1-arylamide and
N-phenylbenzenesulfonamide derivatives as BACE 1
inhibitors. Bioorg Med Chem 16, 10190-10197.
Chirapu SR, Pachaiyappan B, Nural HF, Cheng X, Yuan
H, Lankin DC, Abdul-Hay SO, Thatcher GR, Shen Y,
Kozikowski AP, Petukhov PA (2009) Molecular modeling, synthesis, and activity studies of novel biaryl and
fused-ring BACE1 inhibitors. Bioorg Med Chem Lett 19,
264-274.
Rizzi L, Vaiana N, Sagui F, Genesio E, Pilli E, Porcari
V, Romeo S (2009) Design, synthesis and docking studies
of Hydroxyethylamine and Hydroxyethylsulfide BACE-1
inhibitors. Protein Pept Lett 16, 86-90.
Al-Nadaf A, Abu SG, Taha MO (2010) Elaborate ligandbased pharmacophore exploration and QSAR analysis
guide the synthesis of novel pyridinium-based potent
beta-secretase inhibitory leads. Bioorg Med Chem 18,
3088-3115.
Gutierrez LJ, Enriz RD, Baldoni HA (2010) Structural
and thermodynamic characteristics of the exosite binding pocket on the human BACE1: A molecular modeling
approach. J Phys Chem A 114, 10261-10269.
Liu S, Zhou LH, Wang HQ, Yao ZB (2010) Superimposing the 27 crystal protein/inhibitor complexes of
beta-secretase to calculate the binding affinities by the linear interaction energy method. Bioorg Med Chem Lett 20,
6533-6537.
Pandey A, Mungalpara J, Mohan CG (2010) Comparative molecular field analysis and comparative molecular
similarity indices analysis of hydroxyethylamine derivatives as selective human BACE-1 inhibitor. Mol Divers 14,
39-49.
Salum LB, Valadares NF (2010) Fragment-guided
approach to incorporating structural information into a
CoMFA study: BACE-1 as an example. J Comput Aided
Mol Des 24, 803-817.
Xu W, Chen G, Zhu W, Zuo Z (2010) Molecular docking
and structure-activity relationship studies on benzothiazole based non-peptidic BACE-1 inhibitors. Bioorg Med
Chem Lett 20, 6203-6207.
Xu W, Chen G, Zhu W, Zuo Z (2010) Identification of
a sub-micromolar, non-peptide inhibitor of beta-secretase
with low neural cytotoxicity through in silico screening 7.
Bioorg Med Chem Lett 20, 5763-5766.
Gueto-Tettay C, Drosos JC, Vivas-Reyes R (2011) Quantum mechanics study of the hydroxyethylamines-BACE-1
active site interaction energies. J Comput Aided Mol Des
25, 583-597.
John S, Thangapandian S, Sakkiah S, Lee KW (2011)
Potent BACE-1 inhibitor design using pharmacophore
modeling, in silico screening and molecular docking studies. BMC Bioinformatics 12 (Suppl 1), S28.
Sussman F, Otero JM, Villaverde MC, Castro M,
Dominguez JL, Gonzalez-Louro L, Estevez RJ, Estevez JC
(2011) On a possible neutral charge state for the catalytic
dyad in beta-secretase when bound to hydroxyethylene
transition state analogue inhibitors. J Med Chem 54, 30813085.
Nino H, Garcia-Pintos I, Rodriguez-Borges JE, EscobarCubiella M, Garcia-Mera X, Prado-Prado F (2011) Review
of synthesis, biological assay and QSAR studies of beta-
[770]
[771]
[772]
[773]
[774]
[775]
[776]
[777]
[778]
[779]
[780]
[781]
623
secretase inhibitors. Curr Comput Aided Drug Des 7, 263275.
Al-Tel TH, Semreen MH, Al-Qawasmeh RA, Schmidt MF,
El-Awadi R, Ardah M, Zaarour R, Rao SN, El-Agnaf
O (2011) Design, synthesis, and qualitative structureactivity evaluations of novel beta-secretase inhibitors as
potential Alzheimer’s drug leads. J Med Chem 54, 83738385.
Chiriano G, Sartini A, Mancini F, Andrisano V, Bolognesi
ML, Roberti M, Recanatini M, Carloni P, Cavalli A (2011)
Sequential virtual screening approach to the identification
of small organic molecules as potential BACE-1 inhibitors.
Chem Biol Drug Des 77, 268-271.
Liu S, Fu R, Zhou LH, Chen SP (2012) Application of
consensus scoring and principal component analysis for
virtual screening against beta-secretase (BACE-1). PLoS
One 7, e38086.
Razzaghi-Asl N, Ebadi A, Edraki N, Mehdipour A, Shahabipour S, Miri R (2012) Response surface methodology
in docking study of small molecule BACE-1 inhibitors.
J Mol Model, doi: 10.1007/S00894-012-1424-1 [Epubl
ahead of print].
Barman A, Prabhakar R (2012) Protonation states of the
catalytic dyad of beta-secretase (BACE1) in the presence
of chemically diverse inhibitors: A molecular docking
study. J Chem Inf Model 52, 1275-1287.
Niu Y, Ma C, Jin H, Xu F, Gao H, Liu P, Li Y, Wang C,
Yang G, Xu P (2012) The discovery of novel beta-secretase
inhibitors: Pharmacophore modeling, virtual screening,
and docking studies. Chem Biol Drug Des 79, 972-980.
Nino H, Rodriguez-Borges JE, Garcia-Mera X, PradoPrado F (2012) Review of synthesis, assay, and prediction
of beta and gamma-secretase inhibitors. Curr Top Med
Chem 12, 828-844.
Xu Y, Li MJ, Greenblatt H, Chen W, Paz A, Dym O, Peleg
Y, Chen T, Shen X, He J, Jiang H, Silman I, Sussman JL
(2012) Flexibility of the flap in the active site of BACE1
as revealed by crystal structures and molecular dynamics
simulations. Acta Crystallogr D Biol Crystallogr 68, 1325.
Liu S, Fu R, Cheng X, Chen SP, Zhou LH (2012) Exploring the binding of BACE-1 inhibitors using comparative
binding energy analysis (COMBINE). BMC Struct Biol
12, 21.
Back M, Nyhlen J, Kvarnstrom I, Appelgren S, Borkakoti
N, Jansson K, Lindberg J, Nystrom S, Hallberg A, Rosenquist S, Samuelsson B (2008) Design, synthesis and SAR
of potent statine-based BACE-1 inhibitors: Exploration of
P1 phenoxy and benzyloxy residues. Bioorg Med Chem
16, 9471-9486.
Swahn BM, Holenz J, Kihlstrom J, Kolmodin K, Lindstrom J, Plobeck N, Rotticci D, Sehgelmeble F, Sundstrom
M, Berg S, Falting J, Georgievska B, Gustavsson S, Neelissen J, Ek M, Olsson LL, Berg S (2012) Aminoimidazoles
as BACE-1 inhibitors: The challenge to achieve in vivo
brain efficacy. Bioorg Med Chem Lett 22, 1854-1859.
Swahn BM, Kolmodin K, Karlstrom S, von BS, Soderman
P, Holenz J, Berg S, Lindstrom J, Sundstrom M, Turek D,
Kihlstrom J, Slivo C, Andersson L, Pyring D, Rotticci D,
Ohberg L, Kers A, Bogar K, Bergh M, Olsson LL, Janson
J, Eketjall S, Georgievska B, Jeppsson F, Falting J (2012)
Design and synthesis of beta-secretase (BACE1) inhibitors
with in vivo brain reduction of beta-amyloid peptides.
J Med Chem, doi: 10.1021/jm3009025 [Epubl ahead of
print].
624
[782]
[783]
[784]
[785]
[786]
[787]
[788]
[789]
[790]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G,
Holtzman DM, Ghosh AK, Tang J (2011) Beta-secretase
inhibitor GRL-8234 rescues age-related cognitive decline
in APP transgenic mice. FASEB J 25, 775-784.
Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,
Dunsdon R, East P, Hawkins J, Howes C, Hussain I, Jeffrey P, Maile G, Matico R, Mosley J, Naylor A, O’Brien
A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer
S, Theobald P, Vesey D, Walter DS, Wayne G (2008) Second generation of hydroxyethylamine BACE-1 inhibitors:
Optimizing potency and oral bioavailability. J Med Chem
51, 3313-3317.
Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,
Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain
I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A,
Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S,
Theobald P, Vesey D, Walter DS, Wayne G (2009) Second generation of BACE-1 inhibitors. Part 1: The need for
improved pharmacokinetics. Bioorg Med Chem Lett 19,
3664-3668.
Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon
R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico
R, Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland
P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D,
Walter DS, Wayne G (2009) Second generation of BACE1 inhibitors part 2: Optimisation of the non-prime side
substituent. Bioorg Med Chem Lett 19, 3669-3673.
Charrier N, Clarke B, Cutler L, Demont E, Dingwall C,
Dunsdon R, Hawkins J, Howes C, Hubbard J, Hussain
I, Maile G, Matico R, Mosley J, Naylor A, O’Brien A,
Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S,
Theobald P, Vesey D, Walter DS, Wayne G (2009) Second generation of BACE-1 inhibitors part 3: Towards non
hydroxyethylamine transition state mimetics. Bioorg Med
Chem Lett 19, 3674-3678.
Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter D, Demont E, Howes C, Naylor A,
Jeffrey P, Gonzalez MI, Dingwall C, Michel A, Redshaw
S, Davis JB (2007) Oral administration of a potent and
selective non-peptidic BACE-1 inhibitor decreases betacleavage of amyloid precursor protein and amyloid-beta
production in vivo. J Neurochem 100, 802-809.
Beswick P, Charrier N, Clarke B, Demont E, Dingwall C,
Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I,
Johnson CN, MacPherson D, Maile G, Matico R, Milner
P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell
D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway
S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D,
Walter DS, Ward J, Wayne G (2008) BACE-1 inhibitors
part 3: Identification of hydroxy ethylamines (HEAs) with
nanomolar potency in cells. Bioorg Med Chem Lett 18,
1022-1026.
Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A,
Hawkins J, Hussain I, MacPherson D, Maile G, Matico R,
Milner P, Mosley J, Naylor A, O’Brien A, Redshaw S, Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S, Stemp
G, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J,
Wayne G (2008) BACE-1 inhibitors part 1: Identification
of novel hydroxy ethylamines (HEAs). Bioorg Med Chem
Lett 18, 1011-1016.
Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A,
Hawkins J, Hussain I, MacPherson D, Maile G, Matico
R, Milner P, Mosley J, Naylor A, O’Brien A, Redshaw
S, Riddell D, Rowland P, Soleil V, Smith KJ, Stanway S,
Stemp G, Sweitzer S, Theobald P, Vesey D, Walter DS,
[791]
[792]
[793]
[794]
[795]
[796]
[797]
[798]
[799]
[800]
[801]
[802]
Ward J, Wayne G (2008) BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced
peptidic character. Bioorg Med Chem Lett 18, 10171021.
Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon
R, Hawkins J, Howes C, Hussain I, Maile G, Matico R,
Mosley J, Naylor A, O’Brien A, Redshaw S, Rowland
P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D,
Walter DS, Wayne G (2010) BACE-1 hydroxyethylamine
inhibitors using novel edge-to-face interaction with Arg296. Bioorg Med Chem Lett 20, 4639-4644.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM,
Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson
BM, Stout SL, Timm DE, Smith LE, Gonzales CR, Nakano
M, Jhee SS, Yen M, Ereshefsky L, Lindstrom TD, Calligaro DO, Cocke PJ, Greg HD, Friedrich S, Citron M,
Audia JE (2011) Robust central reduction of amyloid-beta
in humans with an orally available, non-peptidic betasecretase inhibitor. J Neurosci 31, 16507-16516.
Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita T,
Hirode M, Sagayama M, Maeda R, Kawamoto M, Hirai
K, Terauchi J, Sakura Y, Kakihana M, Kato K, Iwatsubo T,
Miyamoto M (2010) A noncompetitive BACE1 inhibitor
TAK-070 ameliorates Abeta pathology and behavioral
deficits in a mouse model of Alzheimer’s disease. J Neurosci 30, 11157-11166.
Takahashi H, Fukumoto H, Maeda R, Terauchi J, Kato
K, Miyamoto M (2010) Ameliorative effects of a noncompetitive BACE1 inhibitor TAK-070 on Abeta peptide
levels and impaired learning behavior in aged rats. Brain
Res 1361, 146-156.
Yang W, Lu W, Lu Y, Zhong M, Sun J, Thomas AE, Wilkinson JM, Fucini RV, Lam M, Randal M, Shi XP, Jacobs
JW, McDowell RS, Gordon EM, Ballinger MD (2006)
Aminoethylenes: A tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1.
J Med Chem 49, 839-842.
Yang W, Fucini RV, Fahr BT, Randal M, Lind KE, Lam
MB, Lu W, Lu Y, Cary DR, Romanowski MJ, Colussi D,
Pietrak B, Allison TJ, Munshi SK, Penny DM, Pham P, Sun
J, Thomas AE, Wilkinson JM, Jacobs JW, McDowell RS,
Ballinger MD (2009) Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering. Biochemistry
48, 4488-4496.
Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, De
SB, Steiner H, Haass C, Wolfe MS (2007) Active gammasecretase complexes contain only one of each component.
J Biol Chem 282, 33985-33993.
Haass C, Steiner H (2002) Alzheimer disease gammasecretase: A complex story of GxGD-type presenilin
proteases. Trends Cell Biol 12, 556-562.
Sisodia SS, St George-Hyslop PH (2002) gammaSecretase, Notch, Abeta and Alzheimer’s disease: Where
do the presenilins fit in? Nat Rev Neurosci 3, 281-290.
Tsai JY, Wolfe MS, Xia W (2002) The search for gammasecretase and development of inhibitors. Curr Med Chem
9, 1087-1106.
Knappenberger KS, Tian G, Ye X, Sobotka-Briner
C, Ghanekar SV, Greenberg BD, Scott CW (2004)
Mechanism of gamma-secretase cleavage activation: Is
gamma-secretase regulated through autoinhibition involving the presenilin-1 exon 9 loop?. Biochemistry 43,
6208-6218.
Steiner H (2004) Uncovering gamma-secretase. Curr
Alzheimer Res 1, 175-181.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[803]
[804]
[805]
[806]
[807]
[808]
[809]
[810]
[811]
[812]
[813]
[814]
[815]
[816]
[817]
[818]
Steiner H, Than M, Bode W, Haass C (2006) Pore-forming
scissors? A first structural glimpse of gamma-secretase.
Trends Biochem Sci 31, 491-493.
Steiner H (2008) The catalytic core of gamma-secretase:
Presenilin revisited. Curr Alzheimer Res 5, 147-157.
Steiner H, Winkler E, Haass C (2008) Chemical crosslinking provides a model of the gamma-secretase complex
subunit architecture and evidence for close proximity of
the C-terminal fragment of presenilin with APH-1. J Biol
Chem 283, 34677-34686.
Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ,
Li H (2006) Electron microscopic structure of purified,
active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A
103, 6889-6894.
Sato C, Morohashi Y, Tomita T, Iwatsubo T (2006) Structure of the catalytic pore of gamma-secretase probed by
the accessibility of substituted cysteines. J Neurosci 26,
12081-12088.
Sato C, Takagi S, Tomita T, Iwatsubo T (2008) The
C-terminal PAL motif and transmembrane domain 9 of
presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci 28, 62646271.
Kreft AF, Martone R, Porte A (2009) Recent advances in
the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer’s
disease. J Med Chem 52, 6169-6188.
Krishnaswamy S, Verdile G, Groth D, Kanyenda L, Martins RN (2009) The structure and function of Alzheimer’s
gamma secretase enzyme complex. Crit Rev Clin Lab Sci
46, 282-301.
Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo
T (2010) Participation of transmembrane domain 1 of
presenilin 1 in the catalytic pore structure of the gammasecretase. J Neurosci 30, 15943-15950.
Wolfe MS (2010) Structure, mechanism and inhibition of
gamma-secretase and presenilin-like proteases. Biol Chem
391, 839-847.
Page RM, Baumann K, Tomioka M, Perez-Revuelta BI,
Fukumori A, Jacobsen H, Flohr A, Luebbers T, Ozmen
L, Steiner H, Haass C (2008) Generation of Abeta38
and Abeta42 is independently and differentially affected
by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem 283,
677-683.
Page RM, Gutsmiedl A, Fukumori A, Winkler E, Haass C,
Steiner H (2010) Beta-amyloid precursor protein mutants
respond to gamma-secretase modulators. J Biol Chem 285,
17798-17810.
Takami M, Nagashima Y, Sano Y, Ishihara S, MorishimaKawashima M, Funamoto S, Ihara Y (2009) gammaSecretase: Successive tripeptide and tetrapeptide release
from the transmembrane domain of beta-carboxyl terminal
fragment. J Neurosci 29, 13042-13052.
Tolia A, De Strooper B (2009) Structure and function of
gamma-secretase. Semin Cell Dev Biol 20, 211-218.
Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen
A, Benurwar M, Borgers M, Lismont S, Zhou L, Van CS,
Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H,
Schymkowitz J, Rousseau F, Broersen K, De Strooper B
(2012) The mechanism of gamma-Secretase dysfunction
in familial Alzheimer disease. EMBO J 31, 2261-2274.
De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts
K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray
[819]
[820]
[821]
[822]
[823]
[824]
[825]
[826]
[827]
[828]
[829]
[830]
[831]
[832]
625
WJ, Goate A, Kopan R (1999) A presenilin-1-dependent
gamma-secretase-like protease mediates release of Notch
intracellular domain. Nature 398, 518-522.
Lundkvist J, Naslund J (2007) Gamma-secretase: A complex target for Alzheimer’s disease. Curr Opin Pharmacol
7, 112-118.
Lleo A (2008) Activity of gamma-secretase on substrates
other than APP. Curr Top Med Chem 8, 9-16.
Oehlrich D, Berthelot DJ, Gijsen HJ (2011) gammasecretase modulators as potential disease modifying
anti-Alzheimer’s drugs. J Med Chem 54, 669-698.
Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ,
Schirtzinger LM, Berridge BR, Gao H, Higgins MA, May
PC, Ryan TP (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase
inhibitor. J Biol Chem 278, 46107-46116.
Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan
F, Gadient R, Jacobs RT, Zacco A, Greenberg B, Ciaccio
PJ (2004) Modulation of notch processing by gammasecretase inhibitors causes intestinal goblet cell metaplasia
and induction of genes known to specify gut secretory
lineage differentiation. Toxicol Sci 82, 341-358.
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara
T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang
L, Higgins GA, Parker EM (2004) Chronic treatment with
the gamma-secretase inhibitor LY-411,575 inhibits betaamyloid peptide production and alters lymphopoiesis and
intestinal cell differentiation. J Biol Chem 279, 1287612882.
Grosveld GC (2009) Gamma-secretase inhibitors: Notch
so bad. Nat Med 15, 20-21.
Rao SS, O’Neil J, Liberator CD, Hardwick JS, Dai X,
Zhang T, Tyminski E, Yuan J, Kohl NE, Richon VM, Van
der Ploeg LH, Carroll PM, Draetta GF, Look AT, Strack
PR, Winter CG (2009) Inhibition of NOTCH signaling
by gamma secretase inhibitor engages the RB pathway
and elicits cell cycle exit in T-cell acute lymphoblastic
leukemia cells. Cancer Res 69, 3060-3068.
Jorissen E, De Strooper B (2010) Gamma-secretase and
the intramembrane proteolysis of Notch. Curr Top Dev
Biol 92, 201-230.
Oh SY, Ellenstein A, Chen CD, Hinman JD, Berg EA,
Costello CE, Yamin R, Neve RL, Abraham CR (2005)
Amyloid precursor protein interacts with notch receptors.
J Neurosci Res 82, 32-42.
Dovey HF, John V, Anderson JP, Chen LZ, de Saint AP,
Fang LY, Freedman SB, Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL,
Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z,
Lieberburg IM, Motter RN, Mutter LC, Nietz J, Quinn KP,
Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung
JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN, Britton TC, Clemens
JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson
KS, Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Audia JE (2001) Functional
gamma-secretase inhibitors reduce beta-amyloid peptide
levels in brain. J Neurochem 76, 173-181.
Beher D, Shearman MS (2002) Gamma-secretase inhibition. Biochem Soc Trans 30, 534-537.
Josien H (2002) Recent advances in the development of
gamma-secretase inhibitors. Curr Opin Drug Discov Devel
5, 513-525.
Rochette MJ, Murphy MP (2002) Gamma-secretase: Substrates and inhibitors. Mol Neurobiol 26, 81-95.
626
[833]
[834]
[835]
[836]
[837]
[838]
[839]
[840]
[841]
[842]
[843]
[844]
[845]
[846]
[847]
[848]
[849]
[850]
[851]
[852]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Wolfe MS, Esler WP, Das C (2002) Continuing strategies for inhibiting Alzheimer’s gamma-secretase. J Mol
Neurosci 19, 83-87.
Xu M, Lai MT, Huang Q, Muzio-Mower J, Castro JL,
Harrison T, Nadin A, Neduvelil JG, Shearman MS, Shafer
JA, Gardell SJ, Li YM (2002) gamma-Secretase: Characterization and implication for Alzheimer disease therapy.
Neurobiol Aging 23, 1023-1030.
Harrison T, Beher D (2003) gamma-Secretase inhibitors–
from molecular probes to new therapeutics? Prog Med
Chem 41, 99-127.
Harrison T, Churcher I, Beher D (2004) gamma-Secretase
as a target for drug intervention in Alzheimer’s disease.
Curr Opin Drug Discov Devel 7, 709-719.
Marjaux E, De Strooper B (2004) Gamma-Secretase
inhibitors: Still in the running as Alzheimer’s therapeutics.
Drug Discov Today Therap Strategies 1, 1-6.
Churcher I, Beher D (2005) Gamma-secretase as a therapeutic target for the treatment of Alzheimer’s disease. Curr
Pharm Des 11, 3363-3382.
Pollack SJ, Lewis H (2005) Secretase inhibitors for
Alzheimer’s disease: Challenges of a promiscuous protease. Curr Opin Investig Drugs 6, 35-47.
Barten DM, Meredith JE Jr, Zaczek R, Houston JG,
Albright CF (2006) Gamma-secretase inhibitors for
Alzheimer’s disease: Balancing efficacy and toxicity.
Drugs R D 7, 87-97.
Evin G, Sernee MF, Masters CL (2006) Inhibition
of gamma-secretase as a therapeutic intervention for
Alzheimer’s disease: Prospects, limitations and strategies.
CNS Drugs 20, 351-372.
Tomita T, Iwatsubo T (2006) gamma-secretase as a therapeutic target for treatment of Alzheimer’s disease. Curr
Pharm Des 12, 661-670.
Ziani-Cherif C, Mostefa-Kara B, Brixi-Gormat FZ
(2006) Gamma-secretase as a pharmacological target in
Alzheimer disease research: When, why and how? Curr
Pharm Des 12, 4313-4335.
Olson RE, Albright CF (2008) Recent progress in the
medicinal chemistry of gamma-secretase inhibitors. Curr
Top Med Chem 8, 17-33.
Jakob-Roetne R, Jacobsen H (2009) Alzheimer’s disease:
From pathology to therapeutic approaches. Angew Chem
Int Ed Engl 4, 3030-3059.
Wu WL, Zhang L (2009) Gamma-Secretase inhibitors for
the treatment of Alzheimer’s disease. Drug Dev Res 70,
94-100.
Woo HN, Park JS, Gwon AR, Arumugam TV, Jo DG
(2009) Alzheimer’s disease and Notch signaling. Biochem
Biophys Res Commun 390, 1093-1097.
Augelli-Szafran CE, Wei HX, Lu D, Zhang J, Gu Y,
Yang T, Osenkowski P, Ye W, Wolfe MS (2010) Discovery of notch-sparing gamma-secretase inhibitors. Curr
Alzheimer Res 7, 207-209.
Guardia-Laguarta C, Pera M, Lleo A (2010) gammaSecretase as a therapeutic target in Alzheimer’s disease.
Curr Drug Targets 11, 506-517.
Lleo A, Saura CA (2011) gamma-secretase substrates and
their implications for drug development in Alzheimer’s
disease. Curr Top Med Chem 11, 1513-1527.
Wolfe MS (2012) gamma-Secretase inhibitors and modulators for Alzheimer’s disease. J Neurochem 120(Suppl
1), 89-98.
Barthet G, Georgakopoulos A, Robakis NK (2012)
Cellular mechanisms of gamma-secretase substrate selec-
[853]
[854]
[855]
[856]
[857]
[858]
[859]
[860]
[861]
[862]
[863]
[864]
[865]
[866]
tion, processing and toxicity. Prog Neurobiol 98, 166175.
Imbimbo BP (2008) Therapeutic potential of gammasecretase inhibitors and modulators. Curr Top Med Chem
8, 54-61.
Wolfe MS (2008) Gamma-secretase inhibition and modulation for Alzheimer’s disease. Curr Alzheimer Res 5,
158-164.
Wolfe MS (2008) Inhibition and modulation of gammaSecretase for Alzheimer’s disease. Neurotherapeutics 5,
391-398.
Tomita T (2009) Secretase inhibitors and modulators for
Alzheimer’s disease treatment. Expert Rev Neurother 9,
661-679.
Bergmans BA, De Strooper B (2010) gamma-secretases:
From cell biology to therapeutic strategies. Lancet Neurol
9, 215-226.
Ross JS, Imbimbo BP (2010) Are gamma-secretase
inhibitors detrimental for Alzheimer’s disease patients?.
J Alzheimers Dis 22, 401-404.
Imbimbo BP, Giardina GA (2011) gamma-secretase
inhibitors and modulators for the treatment of Alzheimer’s
disease: Disappointments and hopes. Curr Top Med Chem
11, 1555-1570.
Imbimbo BP, Panza F, Frisardi V, Solfrizzi V, D’Onofrio
G, Logroscino G, Seripa D, Pilotto A (2011) Therapeutic
intervention for Alzheimer’s disease with gammasecretase inhibitors: Still a viable option? Expert Opin
Investig Drugs 20, 325-341.
Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino
G, Santamato A, Greco A, Seripa D, Pilotto A (2011)
Interacting with gamma-secretase for treating Alzheimer’s
disease: From inhibition to modulation. Curr Med Chem
18, 5430-5447.
Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma
E, Mazell C, Bhat NR, Kindy MS, Lahiri DK, Pappolla MA
(2011) Targets for AD treatment: Conflicting messages
from gamma-secretase inhibitors. J Neurochem 117, 359374.
D’Onofrio G, Panza F, Frisardi V, Solfrizzi V, Imbimbo
BP, Paroni G, Cascavilla L, Seripa D, Pilotto A
(2012) Advances in the identification of gamma-secretase
inhibitors for the treatment of Alzheimer’s disease. Expert
Opin Drug Discov 7, 19-37.
Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R,
Croop R, Castaneda L, Gu H, Wong O, Li H, Berman
RM, Smith C, Albright CF, Dockens RC (2012) Multicenter, randomized, double-blind, placebo-controlled,
single-ascending dose study of the oral gamma-secretase
inhibitor BMS-708163 (Avagacestat): Tolerability profile, pharmacokinetic parameters, and pharmacodynamic
markers. Clin Ther 34, 654-667.
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody
M, Richter RW, Soininen H, Thein S, Shiovitz T, Pilcher
G, Colby S, Rollin L, Dockens R, Pachai C, Portelius
E, Andreasson U, Blennow K, Soares H, Albright C,
Feldman HH, Berman RM (2012) Safety and tolerability
of the gamma-secretase inhibitor avagacestat in a Phase 2
study of mild to moderate Alzheimer disease. Arch Neurol, doi: 10.1001/archneurol.2012.2194 [Epubl ahead of
print].
Gu H, Deng Y, Wang J, Aubry AF, Arnold ME
(2010) Development and validation of sensitive and
selective LC-MS/MS methods for the determination of BMS-708163, a gamma-secretase inhibitor,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[866]
[867]
[868]
[869]
[870]
[871]
[872]
[873]
[874]
[875]
in plasma and cerebrospinal fluid using deprotonated
or formate adduct ions as precursor ions. J Chromatogr B Analyt Technol Biomed Life Sci 878, 23192326.
[3]Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang
SP, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith
C, Albright CF, Tong G (2012) A Placebo-Controlled,
Multiple Ascending Dose Study to Evaluate the Safety,
Pharmacokinetics and Pharmacodynamics of Avagacestat
(BMS-708163) in Healthy Young and Elderly Subjects.
Clin Pharmacokinet 51, 681-693.
Prasad CV, Wallace OB, Noonan JW, Sloan CP, Lau W,
Vig S, Parker MF, Smith DW, Hansel SB, Polson CT,
Barten DM, Felsenstein KM, Roberts SB (2004) Hydroxytriamides as potent gamma-secretase inhibitors. Bioorg
Med Chem Lett 14, 1917-1921.
Prasad CV, Vig S, Smith DW, Gao Q, Polson CT, Corsa JA,
Guss VL, Loo A, Barten DM, Zheng M, Felsenstein KM,
Roberts SB (2004) 2,3-Benzodiazepin-1,4-diones as peptidomimetic inhibitors of gamma-secretase. Bioorg Med
Chem Lett 14, 3535-3538.
Prasad CV, Zheng M, Vig S, Bergstrom C, Smith DW, Gao
Q, Yeola S, Polson CT, Corsa JA, Guss VL, Loo A, Wang
J, Sleczka BG, Dangler C, Robertson BJ, Hendrick JP,
Roberts SB, Barten DM (2007) Discovery of (S)-2-((S)2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5yl) propanamide (BMS-433796): A gamma-secretase
inhibitor with Abeta lowering activity in a transgenic
mouse model of Alzheimer’s disease. Bioorg Med Chem
Lett 17, 4006-4011.
Yan XX, Li T, Rominger CM, Prakash SR, Wong PC,
Olson RE, Zaczek R, Li YW (2004) Binding sites of
gamma-secretase inhibitors in rodent brain: Distribution,
postnatal development, and effect of deafferentation. J
Neurosci 24, 2942-2952.
Thompson LA, Liauw AY, Ramanjulu MM, KasireddyPolam P, Mercer SE, Maduskuie TP, Glicksman M, Roach
AH, Meredith JE, Liu RQ, Combs AP, Higaki JN, Cordell
B, Seiffert D, Zaczek RC, Robertson DW, Olson RE
(2006) Synthesis and evaluation of succinoyl-caprolactam
gamma-secretase inhibitors. Bioorg Med Chem Lett 16,
2357-2363.
Parker MF, Barten DM, Bergstrom CP, Bronson JJ, Corsa
JA, Deshpande MS, Felsenstein KM, Guss VL, Hansel
SB, Johnson G, Keavy DJ, Lau WY, Mock J, Prasad
CV, Polson CT, Sloan CP, Smith DW, Wallace OB,
Wang HH, Williams A, Zheng M (2007) N-(5-chloro2-(hydroxymethyl)-N-alkyl-arylsulfonamides as gammasecretase inhibitors. Bioorg Med Chem Lett 17, 4432-4436.
Parker MF, Bronson JJ, Barten DM, Corsa JA, Du W,
Felsenstein KM, Guss VL, Izzarelli D, Loo A, McElhone KE, Marcin LR, Padmanabha R, Pak R, Polson CT,
Toyn JH, Varma S, Wang J, Wong V, Zheng M, Roberts
SB (2007) Amino-caprolactam derivatives as gammasecretase inhibitors. Bioorg Med Chem Lett 17, 5790-5795.
Yang MG, Shi JL, Modi DP, Wells J, Cochran BM, Wolf
MA, Thompson LA, Ramanjulu MM, Roach AH, Zaczek
R, Robertson DW, Wexler RR, Olson RE (2007) Design
and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase
inhibitors. Bioorg Med Chem Lett 17, 3910-3915.
Bergstrom CP, Sloan CP, Wang HH, Parker MF, Smith DW,
Zheng M, Hansel SB, Polson CT, Barber LE, Bursuker I,
Guss VL, Corsa JA, Barten DM, Felsenstein KM, Roberts
[876]
[877]
[878]
[879]
[880]
[881]
[882]
[883]
[884]
[885]
[886]
627
SB (2008) Nitrogen-appended N-alkylsulfonamides as
inhibitors of gamma-secretase. Bioorg Med Chem Lett 18,
175-178.
Bergstrom CP, Sloan CP, Lau WY, Smith DW, Zheng
M, Hansel SB, Polson CT, Corsa JA, Barten DM,
Felsenstein KM, Roberts SB (2008) Carbamate-appended
N-alkylsulfonamides as inhibitors of gamma-secretase.
Bioorg Med Chem Lett 18, 464-468.
Gillman KW, Starrett JE, Parker MF, Xie K, Bronson
JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA,
Williams R, Meredith JE, Burton CR, Barten DM, Toyn
JH, Roberts SB, Lentz KA, Houston JG, Zaczek R,
Albright CF, Decicco CP, Macor JE, Olson RE (2010) Discovery and evaluation of BMS-708163, a potent, selective
and orally bioavailable gamma-secretase inhibitor. ACS
Med Chem Lett 1, 120-124.
Panza F, Frisardi V, Imbimbo BP, Capurso C, Logroscino
G, Sancarlo D, Seripa D, Vendemiale G, Pilotto A, Solfrizzi V (2010) Review: Gamma-Secretase inhibitors for
the treatment of Alzheimer’s disease: The current state.
CNS Neurosci Ther 16, 272-284.
Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T,
Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL (2000)
L-685,458, an aspartyl protease transition state mimic, is a
potent inhibitor of amyloid beta-protein precursor gammasecretase activity. Biochemistry 39, 8698-8704.
Nadin A, Sanchez Lopez JM, Neduvelil JG, Thomas
SR (2001) A stereocontrolled synthesis of 2Rbenzyl-5S-tert-butoxycarbonyl-amino-4R-(tert- butyldimethylsilanyloxy)-6-phenyl-hexanoic acid (Phe-Phe
hydroxy-ethylene dipeptide isostere). Tetrahedron 57,
1861-1864.
Nadin A, Owens AP, Castro JL, Harrison T, Shearman
MS (2003) Synthesis and gamma-secretase activity of
APP substrate-based hydroxyethylene dipeptide isosteres.
Bioorg Med Chem Lett 13, 37-41.
Xu M, Lai MT, Huang Q, Muzio-Mower J, Castro JL,
Harrison T, Nadin A, Neduvelil JG, Shearman MS, Shafer
JA, Gardell SJ, Li YM (2002) gamma-Secretase: Characterization and implication for Alzheimer disease therapy.
Neurobiol Aging 23, 1023-1030.
Churcher I, Ashton K, Butcher JW, Clarke EE, Harrison
T, Lewis HD, Owens AP, Teall MR, Williams S, Wrigley
JD (2003) A new series of potent benzodiazepine gammasecretase inhibitors. Bioorg Med Chem Lett 13, 179183.
Churcher I, Williams S, Kerrad S, Harrison T, Castro JL,
Shearman MS, Lewis HD, Clarke EE, Wrigley JD, Beher
D, Tang YS, Liu W (2003) Design and synthesis of highly
potent benzodiazepine gamma-secretase inhibitors: Preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-1-methyl-2-oxo-5-phenyl-2,
3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide
by use of an asymmetric Ireland-Claisen rearrangement.
J Med Chem 46, 2275-2278.
Churcher I, Beher D, Best JD, Castro JL, Clarke EE,
Gentry A, Harrison T, Hitzel L, Kay E, Kerrad S, Lewis
HD, Morentin-Gutierrez P, Mortishire-Smith R, Oakley
PJ, Reilly M, Shaw DE, Shearman MS, Teall MR, Williams
S, Wrigley JD (2006) 4-substituted cyclohexyl sulfones as
potent, orally active gamma-secretase inhibitors. Bioorg
Med Chem Lett 16, 280-284.
Scott JP, Lieberman DR, Beureux OM, Brands KM, Davies
AJ, Gibson AW, Hammond DC, McWilliams CJ, Stewart
GW, Wilson RD, Dolling UH (2007) A practical synthesis
628
[887]
[888]
[889]
[890]
[891]
[892]
[893]
[894]
[895]
[896]
[897]
[898]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
of a gamma-secretase inhibitor. J Org Chem 72, 41494155.
Owens AP, Nadin A, Talbot AC, Clarke EE, Harrison
T, Lewis HD, Reilly M, Wrigley JD, Castro JL (2003)
High affinity, bioavailable 3-amino-1,4-benzodiazepinebased gamma-secretase inhibitors. Bioorg Med Chem Lett
13, 4143-4145.
Lewis SJ, Smith AL, Neduvelil JG, Stevenson GI, Lindon
MJ, Jones AB, Shearman MS, Beher D, Clarke E, Best
JD, Peachey JE, Harrison T, Castro JL (2005) A novel
series of potent gamma-secretase inhibitors based on a
benzobicyclo[4.2.1]nonane core. Bioorg Med Chem Lett
15, 373-378.
Sparey T, Beher D, Best J, Biba M, Castro JL, Clarke
E, Hannam J, Harrison T, Lewis H, Madin A, Shearman
M, Sohal B, Tsou N, Welch C, Wrigley J (2005) Cyclic
sulfamide gamma-secretase inhibitors. Bioorg Med Chem
Lett 15, 4212-4216.
Sparey T, Clarke E, Hannam J, Harrison T, Madin A,
Shearman M, Sohal B (2008) Sulfonamide derivatives of
bridgehead substituted bicyclo[4.2.1]nonanes as gammasecretase inhibitors. Bioorg Med Chem Lett 18, 375-379.
Jelley RA, Elliott J, Gibson KR, Harrison T, Beher
D, Clarke EE, Lewis HD, Shearman M, Wrigley JD
(2006) 3-Substituted gem-cyclohexane sulfone based
gamma-secretase inhibitors for Alzheimer’s disease: Conformational analysis and biological activity. Bioorg Med
Chem Lett 16, 3839-3842.
Scott JP, Oliver SF, Brands KM, Brewer SE, Davies
AJ, Gibb AD, Hands D, Keen SP, Sheen FJ, Reamer
RA, Wilson RD, Dolling UH (2006) Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting
substrate-controlled intramolecular nitrile oxide-olefin
cycloaddition. J Org Chem 71, 3086-3092.
Shaw D, Best J, Dinnell K, Nadin A, Shearman M, Pattison
C, Peachey J, Reilly M, Williams B, Wrigley J, Harrison T
(2006) 3,4-Fused cyclohexyl sulfones as gamma-secretase
inhibitors. Bioorg Med Chem Lett 16, 3073-3077.
Davies AJ, Scott JP, Bishop BC, Brands KM, Brewer
SE, Dasilva JO, Dormer PG, Dolling UH, Gibb AD,
Hammond DC, Lieberman DR, Palucki M, Payack JF
(2007) A novel crystallization-induced diastereomeric
transformation based on a reversible carbon-sulfur bond
formation. Application to the synthesis of a gammasecretase inhibitor. J Org Chem 72, 4864-4871.
Josien H, Bara T, Rajagopalan M, Asberom T, Clader JW,
Favreau L, Greenlee WJ, Hyde LA, Nomeir AA, Parker
EM, Pissarnitski DA, Song L, Wong GT, Zhang L, Zhang
Q, Zhao Z (2007) Small conformationally restricted piperidine N-arylsulfonamides as orally active gamma-secretase
inhibitors. Bioorg Med Chem Lett 17, 5330-5335.
Josien H, Bara T, Rajagopalan M, Clader JW, Greenlee
WJ, Favreau L, Hyde LA, Nomeir AA, Parker EM, Song
L, Zhang L, Zhang Q (2009) Novel orally active morpholine N-arylsulfonamides gamma-secretase inhibitors with
low CYP 3A4 liability. Bioorg Med Chem Lett 19, 60326037.
Keown LE, Collins I, Cooper LC, Harrison T, Madin A,
Mistry J, Reilly M, Shaimi M, Welch CJ, Clarke EE, Lewis
HD, Wrigley JD, Best JD, Murray F, Shearman MS (2009)
Novel orally bioavailable gamma-secretase inhibitors
with excellent in vivo activity. J Med Chem 52, 34413444.
Sasikumar TK, Qiang L, Burnett DA, Cole D, Xu R, Li H,
Greenlee WJ, Clader. J, Zhang L, Hyde L (2010) Tricyclic
[899]
[900]
[901]
[902]
[903]
[904]
[905]
[906]
[907]
[908]
[909]
[910]
[911]
[912]
sulfones as orally active gamma-secretase inhibitors: Synthesis and structure-activity relationship studies. Bioorg
Med Chem Lett 20, 3632-3635.
Sasikumar TK, Burnett DA, Asberom T, Wu WL, Bennett
C, Cole D, Xu R, Greenlee WJ, Clader J, Zhang L, Hyde
L (2010) Tetracyclic sulfones as potent gamma-secretase
inhibitors: Synthesis and structure-activity relationship
studies. Bioorg Med Chem Lett 20, 3645-3648.
Li H, Xu R, Cole D, Clader JW, Greenlee WJ, Nomeir AA,
Song L, Zhang L (2010) Design, synthesis, and structureactivity relationship studies of N-arylsulfonyl morpholines
as gamma-secretase inhibitors. Bioorg Med Chem Lett 20,
6606-6609.
Lee J, Song L, Terracina G, Bara T, Josien H, Asberom T,
Sasikumar TK, Burnett DA, Clader J, Parker EM, Zhang
L (2011) Identification of presenilin 1-selective gammasecretase inhibitors with reconstituted gamma-secretase
complexes. Biochemistry 50, 4973-4980.
Wu WL, Domalski M, Burnett DA, Josien H, Bara T,
Rajagopalan M, Xu R, Clader J, Greenlee WJ, Brunskill A, Hyde LA, Del Vecchio RA, Cohen-Williams ME,
Song L, Lee J, Terracina G, Zhang Q, Nomeir A, Parker
EM, Zhang L (2012) Discovery of SCH-900229, a potent
presenilin 1 selective gamma-secretase inhibitor for the
treatment of Alzheimer’s disease. ACS Med Chem Lett,
doi: 10.1021/ml300044f [Epubl ahead of print].
Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO,
Selkoe DJ (1998) A substrate-based difluoro ketone
selectively inhibits Alzheimer’s gamma-secretase activity.
J Med Chem 41, 6-9.
Wolfe MS, Xia W, Moore CL, Leatherwood DD,
Ostaszewski B, Rahmati T, Donkor IO, Selkoe DJ
(1999) Peptidomimetic probes and molecular modeling suggest that Alzheimer’s gamma-secretase is an
intramembrane-cleaving aspartyl protease 132. Biochemistry 38, 4720-4727.
Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS,
Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe
MS (2000) Transition-state analogue inhibitors of gammasecretase bind directly to presenilin-1. Nat Cell Biol 2,
428-434.
Moore CL, Leatherwood DD, Diehl TS, Selkoe DJ, Wolfe
MS (2000) Difluoro ketone peptidomimetics suggest a
large S1 pocket for Alzheimer’s gamma-secretase: Implications for inhibitor design. J Med Chem 43, 3434-3442.
Moore CL, Diehl TS, Selkoe DJ, Wolfe MS (2000)
Toward the characterization and identification of gammasecretases using transition-state analogue inhibitors. Ann
N Y Acad Sci 920, 197-205.
Das C, Berezovska O, Diehl TS, Genet C, Buldyrev I,
Tsai JY, Hyman BT, Wolfe MS (2003) Designed helical
peptides inhibit an intramembrane protease. J Am Chem
Soc 125, 11794-11795.
Kornilova AY, Das C, Wolfe MS (2003) Differential effects
of inhibitors on the gamma-secretase complex. Mechanistic implications. J Biol Chem 278, 16470-16473.
Bakshi P, Wolfe MS (2004) Stereochemical analysis of
(hydroxyethyl)urea peptidomimetic inhibitors of gammasecretase. J Med Chem 47, 6485-6489.
Bihel F, Das C, Bowman MJ, Wolfe MS (2004) Discovery
of a Subnanomolar helical D-tridecapeptide inhibitor of
gamma-secretase. J Med Chem 47, 3931-3933.
Best JD, Jay MT, Otu F, Churcher I, Reilly
M, Morentin-Gutierrez P, Pattison C, Harrison
T, Shearman MS, Atack JR (2006) In vivo
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[913]
[914]
[915]
[916]
[917]
[918]
[919]
[920]
[921]
[922]
characterization of Abeta(40) changes in brain and
cerebrospinal fluid using the novel gamma-secretase
inhibitor
N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat. J Pharmacol Exp
Ther 317, 786-790.
Best JD, Smith DW, Reilly MA, O’Donnell R, Lewis
HD, Ellis S, Wilkie N, Rosahl TW, Laroque PA,
Boussiquet-Leroux C, Churcher I, Atack JR, Harrison
T, Shearman MS (2007) The novel gamma secretase
inhibitor
N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5difluorophenyl)cyclohexyl]-1,1,
1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque
deposition without evidence of notch-related pathology in
the Tg2576 mouse. J Pharmacol Exp Ther 320, 552-558.
Townsend M, Qu Y, Gray A, Wu Z, Seto T, Hutton M,
Shearman MS, Middleton RE (2010) Oral treatment with
a gamma-secretase inhibitor improves long-term potentiation in a mouse model of Alzheimer’s disease. J Pharmacol
Exp Ther 333, 110-119.
Lee J, Song L, Terracina G, Bara T, Josien H, Asberom T,
Sasikumar TK, Burnett DA, Clader J, Parker EM, Zhang
L (2011) Identification of presenilin 1-selective gammasecretase inhibitors with reconstituted gamma-secretase
complexes. Biochemistry 50, 4973-4980.
Teall M, Oakley P, Harrison T, Shaw D, Kay E, Elliott J,
Gerhard U, Castro JL, Shearman M, Ball RG, Tsou NN
(2005) Aryl sulfones: A new class of gamma-secretase
inhibitors. Bioorg Med Chem Lett 15, 2685-2688.
Asberom T, Bara TA, Clader JW, Greenlee WJ, Guzik
HS, Josien HB, Li W, Parker EM, Pissarnitski DA, Song
L, Zhang L, Zhao Z (2007) Tetrahydroquinoline sulfonamides as gamma-secretase inhibitors. Bioorg Med Chem
Lett 17, 205-207.
Asberom T, Zhao Z, Bara TA, Clader JW, Greenlee WJ,
Hyde LA, Josien HB, Li W, McPhail AT, Nomeir AA,
Parker EM, Rajagopalan M, Song L, Wong GT, Zhang L,
Zhang Q, Pissarnitski DA (2007) Discovery of gammasecretase inhibitors efficacious in a transgenic animal
model of Alzheimer’s disease. Bioorg Med Chem Lett 17,
511-516.
Guo T, Gu H, Hobbs DW, Rokosz LL, Stauffer TM, Jacob
B, Clader JW (2007) Design, synthesis, and evaluation
of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors. Bioorg Med Chem
Lett 17, 3010-3013.
Li H, Asberom T, Bara TA, Clader JW, Greenlee WJ,
Josien HB, McBriar MD, Nomeir A, Pissarnitski DA,
Rajagopalan M, Xu R, Zhao Z, Song L, Zhang L
(2007) Discovery of 2,4,6-trisubstituted N-arylsulfonyl
piperidines as gamma-secretase inhibitors. Bioorg Med
Chem Lett 17, 6290-6294.
Pissarnitski DA, Asberom T, Bara TA, Buevich AV, Clader
JW, Greenlee WJ, Guzik HS, Josien HB, Li W, McEwan M, McKittrick BA, Nechuta TL, Parker EM, Sinning
L, Smith EM, Song L, Vaccaro HA, Voigt JH, Zhang L,
Zhang Q, Zhao Z (2007) 2,6-Disubstituted N-arylsulfonyl
piperidines as gamma-secretase inhibitors. Bioorg Med
Chem Lett 17, 57-62.
McBriar MD, Clader JW, Chu I, Del Vecchio RA, Favreau
L, Greenlee WJ, Hyde LA, Nomeir AA, Parker EM, Pissarnitski DA, Song L, Zhang L, Zhao Z (2008) Discovery of
amide and heteroaryl isosteres as carbamate replacements
in a series of orally active gamma-secretase inhibitors.
Bioorg Med Chem Lett 18, 215-219.
[923]
[924]
[925]
[926]
[927]
[928]
[929]
[930]
[931]
629
Vaccaro HA, Zhao Z, Clader JW, Song L, Terracina G,
Zhang L, Pissarnitski DA (2008) Solution-phase parallel synthesis of carbamates as gamma-secretase inhibitors.
J Comb Chem 10, 56-62.
Xu R, Cole D, Asberom T, Bara T, Bennett C, Burnett DA,
Clader J, Domalski M, Greenlee W, Hyde L, Josien H,
Li H, McBriar M, McKittrick B, McPhail AT, Pissarnitski
D, Qiang L, Rajagopalan M, Sasikumar T, Su J, Tang H,
Wu WL, Zhang L, Zhao Z (2010) Design and synthesis
of tricyclic sulfones as gamma-secretase inhibitors with
greatly reduced Notch toxicity. Bioorg Med Chem Lett 20,
2591-2596.
Su J, Tang H, McKittrick BA, Xu R, Clader JW, Greenlee WJ, Hyde L, Zhang L (2011) Synthesis and SAR
study of tricyclic sulfones as gamma-secretase inhibitors:
C-6 and C-8 positions. Bioorg Med Chem Lett 21, 34473451.
Sun ZY, Asberom T, Bara T, Bennett C, Burnett D, Chu
I, Clader J, Cohen-Williams M, Cole D, Czarniecki M,
Durkin J, Gallo G, Greenlee W, Josien H, Huang X, Hyde
L, Jones N, Kazakevich I, Li H, Liu X, Lee J, Maccoss M,
Mandal MB, McCracken T, Nomeir A, Mazzola R, Palani
A, Parker EM, Pissarnitski DA, Qin J, Song L, Terracina
G, Vicarel M, Voigt J, Xu R, Zhang L, Zhang Q, Zhao Z,
Zhu X, Zhu Z (2012) Cyclic hydroxyamidines as amide
isosteres: Discovery of oxadiazolines and oxadiazines as
potent and highly efficacious gamma-secretase modulators
in vivo. J Med Chem 55, 489-502.
Close J, Heidebrecht R Jr, Hendrix J, Li C, Munoz B,
Surdi L, Kattar S, Tempest P, Moses P, Geng X, Hughes
B, Smotrov N, Moxham C, Chapnick J, Kariv I, Nikov G,
Burke JE, Deshmukh S, Jeliazkova-Mecheva V, Leach JK,
Diaz D, Xu L, Yang Z, Kwei G, Moy L, Shah S, Tanga F,
Kenefic C, Savage D, Shearman M, Ball RG, McNevin MJ,
Markarewicz A, Miller T (2012) Lead optimization of 4,4biaryl piperidine amides as gamma-secretase inhibitors.
Bioorg Med Chem Lett 22, 3203-3207.
Burt J (2010) American Chemical Society - 240th national
meeting - chemistry for preventing and combating disease:
Part 1. IDrugs 13, 669-672.
Stepan AF, Subramanyam C, Efremov IV, Dutra JK,
O’Sullivan TJ, Dirico KJ, McDonald WS, Won A, Dorff
PH, Nolan CE, Becker SL, Pustilnik LR, Riddell DR,
Kauffman GW, Kormos BL, Zhang L, Lu Y, Capetta SH,
Green ME, Karki K, Sibley E, Atchison KP, Hallgren AJ,
Oborski CE, Robshaw AE, Sneed B, O’Donnell CJ (2012)
Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent
and orally active gamma-secretase inhibitor. J Med Chem
55, 3414-3424.
Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S,
Amore B, Merchant KM (2003) The gamma-secretase
inhibitor
N-[N-(3,5-difluorophenacetyl)-L-alanyl]-Sphenylglycine t-butyl ester reduces A beta levels in vivo
in plasma and cerebrospinal fluid in young (plaque-free)
and aged (plaque-bearing) Tg2576 mice. J Pharmacol
Exp Ther 305, 864-871.
Lanz TA, Hosley JD, Adams WJ, Merchant KM (2004)
Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576
mice using the gamma-secretase inhibitor N2-[(2S)2-(3,5- difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5methyl-6-oxo -6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]L-alaninamide (LY-411575). J Pharmacol Exp Ther 309,
49-55.
630
[932]
[933]
[934]
[935]
[936]
[937]
[938]
[939]
[940]
[941]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N,
Du P, Piotrowski MA, Brown TM, Nolan CE, Richter
KE, Finley JE, Fei Q, Ebbinghaus CF, Chen YL, Spracklin DK, Tate B, Geoghegan KF, Lau LF, Auperin DD,
Schachter JB (2006) Concentration-dependent modulation
of amyloid-beta in vivo and in vitro using the gammasecretase inhibitor, LY-450139. J Pharmacol Exp Ther
319, 924-933.
Chen YL, Cherry K, Corman ML, Ebbinghaus CF, Gamlath CB, Liston D, Martin BA, Oborski CE, Sahagan
BG (2007) Thiazole-diamides as potent gamma-secretase
inhibitors. Bioorg Med Chem Lett 17, 5518-5522.
Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown
TM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ,
Lanz TA, Liston D, Liu X, Martin BA, Nelson RB, Nolan
CE, Oborski CE, Parker CP, Richter KE, Pozdnyakov N,
Sahagan BG, Schachter JB, Sokolowski SA, Tate B, Wood
DE, Wood KM, Van Deusen JW, Zhang L (2011) Design,
synthesis, and in vivo characterization of a novel series of
tetralin amino imidazoles as gamma-secretase inhibitors:
Discovery of PF-3084014. Bioorg Med Chem Lett 21,
2637-2640.
Stepan AF, Karki K, McDonald WS, Dorff PH, Dutra
JK, Dirico KJ, Won A, Subramanyam C, Efremov IV,
O’Donnell CJ, Nolan CE, Becker SL, Pustilnik LR, Sneed
B, Sun H, Lu Y, Robshaw AE, Riddell D, O’Sullivan
TJ, Sibley E, Capetta S, Atchison K, Hallgren AJ,
Miller E, Wood A, Obach RS (2011) Metabolism-directed
design of oxetane-containing arylsulfonamide derivatives
as gamma-secretase inhibitors. J Med Chem 54, 77727783.
Lubbers T, Flohr A, Jolidon S, vid-Pierson P, Jacobsen H,
Ozmen L, Baumann K (2011) Aminothiazoles as gammasecretase modulators. Bioorg Med Chem Lett 21, 65546558.
Rishton GM, Retz DM, Tempest PA, Novotny J, Kahn S,
Treanor JJ, Lile JD, Citron M (2000) Fenchylamine sulfonamide inhibitors of amyloid beta peptide production
by the gamma-secretase proteolytic pathway: Potential
small-molecule therapeutic agents for the treatment of
Alzheimer’s disease. J Med Chem 43, 2297-2299.
Garofalo AW (2008) Patents targeting g-secretase inhibition and modulation for the treatment of Alzheimer’s
disease: 2004–2008. Expert Opin Ther Patents 18, 693703.
Zhao B, Yu M, Neitzel M, Marugg J, Jagodzinski J, Lee
M, Hu K, Schenk D, Yednock T, Basi G (2008) Identification of gamma-secretase inhibitor potency determinants
on presenilin. J Biol Chem 283, 2927-2938.
Bowers S, Probst GD, Truong AP, Hom RK, Konradi AW,
Sham HL, Garofalo AW, Wong K, Goldbach E, Quinn
KP, Sauer JM, Wallace W, Nguyen L, Hemphill SS, Bova
MP, Basi GS (2009) N-Bridged bicyclic sulfonamides as
inhibitors of gamma-secretase. Bioorg Med Chem Lett 19,
6952-6956.
Truong AP, Aubele DL, Probst GD, Neitzel ML, Semko
CM, Bowers S, Dressen D, Hom RK, Konradi AW,
Sham HL, Garofalo AW, Keim PS, Wu J, Dappen MS,
Wong K, Goldbach E, Quinn KP, Sauer JM, Brigham
EF, Wallace W, Nguyen L, Hemphill SS, Bova MP,
Bard F, Yednock TA, Basi G (2009) Design, synthesis, and structure-activity relationship of novel orally
efficacious pyrazole/sulfonamide based dihydroquinoline
gamma-secretase inhibitors. Bioorg Med Chem Lett 19,
4920-4923.
[942]
[943]
[944]
[945]
[946]
[947]
[948]
[949]
[950]
[951]
Basi GS, Hemphill S, Brigham EF, Liao A, Aubele DL,
Baker J, Barbour R, Bova M, Chen XH, Dappen MS,
Eichenbaum T, Goldbach E, Hawkinson J, Lawler-Herbold
R, Hu K, Hui T, Jagodzinski JJ, Keim PS, Kholodenko D,
Latimer LH, Lee M, Marugg J, Mattson MN, McCauley S,
Miller JL, Motter R, Mutter L, Neitzel ML, Ni H, Nguyen
L, Quinn K, Ruslim L, Semko CM, Shapiro P, Smith J,
Soriano F, Szoke B, Tanaka K, Tang P, Tucker JA, Ye XM,
Yu M, Wu J, Xu YZ, Garofalo AW, Sauer JM, Konradi
AW, Ness D, Shopp G, Pleiss MA, Freedman SB, Schenk
D (2010) Amyloid precursor protein selective gammasecretase inhibitors for treatment of Alzheimer’s disease.
Alzheimers Res Ther 2, 36.
Mattson MN, Neitzel ML, Quincy DA, Semko CM, Garofalo AW, Keim PS, Konradi AW, Pleiss MA, Sham HL,
Brigham EF, Goldbach EG, Zhang H, Sauer JM, Basi
GS (2010) Discovery of sulfonamide-pyrazole gammasecretase inhibitors. Bioorg Med Chem Lett 20, 21482150.
Ye XM, Konradi AW, Smith J, Xu YZ, Dressen D, Garofalo AW, Marugg J, Sham HL, Truong AP, Jagodzinski
J, Pleiss M, Zhang H, Goldbach E, Sauer JM, Brigham
E, Bova M, Basi GS (2010) Discovery of a novel
sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors. Bioorg Med Chem
Lett 20, 2195-2199.
Ye XM, Konradi AW, Smith J, Aubele DL, Garofalo AW,
Marugg J, Neitzel ML, Semko CM, Sham HL, Sun M,
Truong AP, Wu J, Zhang H, Goldbach E, Sauer JM,
Brigham EF, Bova M, Basi GS (2010) Discovery of a novel
sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors (Part II). Bioorg Med
Chem Lett 20, 3502-3506.
Aubele DL, Truong AP, Dressen DB, Probst GD, Bowers S, Mattson MN, Semko CM, Sun M, Garofalo AW,
Konradi AW, Sham HL, Zmolek W, Wong K, Goldbach E, Quinn KP, Sauer JM, Brigham EF, Wallace
W, Nguyen L, Bova MP, Hemphill SS, Basi G (2011)
Design, synthesis and structure-activity relationship of
novel[3.3.1] bicyclic sulfonamide-pyrazoles as potent
gamma-secretase inhibitors. Bioorg Med Chem Lett 21,
5791-5794.
Neitzel ML, Aubele DL, Marugg JL, Jagodzinski JJ, Konradi AW, Pleiss MA, Szoke B, Zmolek W, Goldbach E,
Quinn KP, Sauer JM, Brigham EF, Wallace W, Bova MP,
Hemphill S, Basi G (2011) Amino-caprolactam gammasecretase inhibitors showing potential for the treatment
of Alzheimer’s disease. Bioorg Med Chem Lett 21, 37153720.
Petit A, Bihel F, ves da CC, Pourquie O, Checler F,
Kraus JL (2001) New protease inhibitors prevent gammasecretase-mediated production of Abeta40/42 without
affecting Notch cleavage. Nat Cell Biol 3, 507-511.
Petit A, Pasini A, ves da CC, Ayral E, Hernandez JF,
Dumanchin-Njock C, Phiel CJ, Marambaud P, Wilk S,
Farzan M, Fulcrand P, Martinez J, Andrau D, Checler
F (2003) JLK isocoumarin inhibitors: Selective gammasecretase inhibitors that do not interfere with notch
pathway in vitro or in vivo. J Neurosci Res 74, 370-377.
Chun J, Yin YI, Yang G, Tarassishin L, Li YM (2004)
Stereoselective synthesis of photoreactive peptidomimetic
gamma-secretase inhibitors. J Org Chem 69, 7344-7347.
Kan T, Tominari Y, Rikimaru K, Morohashi Y, Natsugari H, Tomita T, Iwatsubo T, Fukuyama T (2004) Parallel
synthesis of DAPT derivatives and their gamma-secretase-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[952]
[953]
[954]
[955]
[956]
[957]
[958]
[959]
[960]
[961]
[962]
[963]
[964]
inhibitory activity. Bioorg Med Chem Lett 14, 19831985.
Checler F, Alves da Costa C, Ayral E, Andrau D,
Dumanchin C, Farzan M, Hernandez JF, Martinez J,
Lefranc-Jullien S, Marambaud P, Pasini A, Petit A, Phiel
C, Robert P, St George-Hyslop P, Wilk S (2005) JLK
inhibitors: Isocoumarin compounds as putative probes
to selectively target the gamma-secretase pathway. Curr
Alzheimer Res 2, 327-334.
Fuwa H, Hiromoto K, Takahashi Y, Yokoshima S, Kan T,
Fukuyama T, Iwatsubo T, Tomita T, Natsugari H (2006)
Synthesis of biotinylated photoaffinity probes based on
arylsulfonamide gamma-secretase inhibitors. Bioorg Med
Chem Lett 16, 4184-4189.
Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y,
Watanabe N, Sato C, Natsugari H, Fukuyama T, Iwatsubo T, Tomita T (2006) C-terminal fragment of presenilin
is the molecular target of a dipeptidic gamma-secretasespecific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)L-alanyl]-S-phenylglycine t-butyl ester). J Biol Chem 281,
14670-14676.
Yang G, Yin YI, Chun J, Shelton CC, Ouerfelli O, Li YM
(2009) Stereo-controlled synthesis of novel photoreactive
gamma-secretase inhibitors. Bioorg Med Chem Lett 19,
922-925.
Yokoshima S, Abe Y, Watanabe N, Kita Y, Kan T, Iwatsubo T, Tomita T, Fukuyama T (2009) Development of
photoaffinity probes for gamma-secretase equipped with
a nitrobenzenesulfonamide-type cleavable linker. Bioorg
Med Chem Lett 19, 6869-6871.
Hottecke N, Liebeck M, Baumann K, Schubenel R,
Winkler E, Steiner H, Schmidt B (2010) Inhibition of
gamma-secretase by the CK1 inhibitor IC261 does not
depend on CK1delta. Bioorg Med Chem Lett 20, 29582963.
Adeniji AO, Wells RM, Adejare A (2012) Syntheses and
in-vitro evaluation of novel adamantane based gammasecretase inhibitors. Curr Med Chem 19, 2458-2471.
Nino H, Rodriguez-Borges JE, Garcia-Mera X, PradoPrado F (2012) Review of synthesis, assay, and prediction
of beta and gamma-secretase inhibitors. Curr Top Med
Chem 12, 828-844.
Gundersen E, Fan K, Haas K, Huryn D, Steven JJ, Kreft A,
Martone R, Mayer S, Sonnenberg-Reines J, Sun SC, Zhou
H (2005) Molecular-modeling based design, synthesis,
and activity of substituted piperidines as gamma-secretase
inhibitors. Bioorg Med Chem Lett 15, 1891-1894.
Ravi Keerti A, Ashok KB, Parthasarathy T, Uma V (2005)
QSAR studies-potent benzodiazepine gamma-secretase
inhibitors. Bioorg Med Chem 13, 1873-1878.
Clarke EE, Churcher I, Ellis S, Wrigley JD, Lewis HD,
Harrison T, Shearman MS, Beher D (2006) Intra- or intercomplex binding to the gamma-secretase enzyme. A model
to differentiate inhibitor classes. J Biol Chem 281, 3127931289.
Rishton GM, LaBonte K, Williams AJ, Kassam K,
Kolovanov E (2006) Computational approaches to the prediction of blood-brain barrier permeability: A comparative
analysis of central nervous system drugs versus secretase
inhibitors for Alzheimer’s disease. Curr Opin Drug Discov
Devel 9, 303-313.
Sammi T, Silakari O, Ravikumar M (2008) Threedimensional quantitative structure-activity relationship
modeling of gamma-secretase inhibitors using molecular
field analysis. Chem Biol Drug Des 71, 155-166.
[965]
[966]
[967]
[968]
[969]
[970]
[971]
[972]
[973]
631
Sammi T, Silakari O, Ravikumar M (2009) Threedimensional quantitative structure-activity relationship
(3D-QSAR) studies of various benzodiazepine analogues
of gamma-secretase inhibitors. J Mol Model 15, 343-348.
Yang XG, Lv W, Chen YZ, Xue Y (2010) In silico
prediction and screening of gamma-secretase inhibitors
by molecular descriptors and machine learning methods.
J Comput Chem 31, 1249-1258.
Das R, Nachbar RB, Edelstein-Keshet L, Saltzman JS,
Wiener MC, Bagchi A, Bailey J, Coombs D, Simon
AJ, Hargreaves RJ, Cook JJ (2011) Modeling effect of
a gamma-secretase inhibitor on amyloid-beta dynamics
reveals significant role of an amyloid clearance mechanism. Bull Math Biol 73, 230-247.
Comery TA, Martone RL, Aschmies S, Atchison KP,
Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, Marquis
KL (2005) Acute gamma-secretase inhibition improves
contextual fear conditioning in the Tg2576 mouse model
of Alzheimer’s disease. J Neurosci 25, 8898-8902.
Kreft A, Harrison B, Aschmies S, Atchison K, Casebier
D, Cole DC, Diamantidis G, Ellingboe J, Hauze D, Hu
Y, Huryn D, Jin M, Kubrak D, Lu P, Lundquist J, Mann
C, Martone R, Moore W, Oganesian A, Porte A, Riddell
DR, Sonnenberg-Reines J, Stock JR, Sun SC, Wagner E,
Woller K, Xu Z, Zhou H, Steven JJ (2008) Discovery of a
novel series of Notch-sparing gamma-secretase inhibitors.
Bioorg Med Chem Lett 18, 4232-4236.
Mayer SC, Kreft AF, Harrison B, bou-Gharbia M, Antane
M, Aschmies S, Atchison K, Chlenov M, Cole DC, Comery T, Diamantidis G, Ellingboe J, Fan K, Galante R,
Gonzales C, Ho DM, Hoke ME, Hu Y, Huryn D, Jain U, Jin
M, Kremer K, Kubrak D, Lin M, Lu P, Magolda R, Martone
R, Moore W, Oganesian A, Pangalos MN, Porte A, Reinhart P, Resnick L, Riddell DR, Sonnenberg-Reines J, Stock
JR, Sun SC, Wagner E, Wang T, Woller K, Xu Z, Zaleska
MM, Zeldis J, Zhang M, Zhou H, Jacobsen JS (2008) Discovery of begacestat, a Notch-1-sparing gamma-secretase
inhibitor for the treatment of Alzheimer’s disease. J Med
Chem 51, 7348-7351.
Cole DC, Stock JR, Kreft AF, Antane M, Aschmies
SH, Atchison KP, Casebier DS, Comery TA, Diamantidis G, Ellingboe JW, Harrison BL, Hu Y, Jin M,
Kubrak DM, Lu P, Mann CW, Martone RL, Moore
WJ, Oganesian A, Riddell DR, Sonnenberg-Reines J,
Sun SC, Wagner E, Wang Z, Woller KR, Xu Z,
Zhou H, Jacobsen JS (2009) (S)-N-(5-Chlorothiophene2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing
gamma-secretase inhibitor. Bioorg Med Chem Lett 19,
926-929.
Martone RL, Zhou H, Atchison K, Comery T, Xu JZ,
Huang X, Gong X, Jin M, Kreft A, Harrison B, Mayer SC,
Aschmies S, Gonzales C, Zaleska MM, Riddell DR, Wagner E, Lu P, Sun SC, Sonnenberg-Reines J, Oganesian A,
Adkins K, Leach MW, Clarke DW, Huryn D, bou-Gharbia
M, Magolda R, Bard J, Frick G, Raje S, Forlow SB, Balliet
C, Burczynski ME, Reinhart PH, Wan HI, Pangalos MN,
Jacobsen JS (2009) Begacestat (GSI-953): A novel, selective thiophene sulfonamide inhibitor of amyloid precursor
protein gamma-secretase for the treatment of Alzheimer’s
disease. J Pharmacol Exp Ther 331, 598-608.
Pu J, Kreft AF, Aschmies SH, Atchison KP, Berkowitz J,
Caggiano TJ, Chlenov M, Diamantidis G, Harrison BL, Hu
Y, Huryn D, Steven JJ, Jin M, Lipinski K, Lu P, Martone
RL, Morris K, Sonnenberg-Reines J, Riddell DR, Sabalski
632
[974]
[975]
[976]
[977]
[978]
[979]
[980]
[981]
[982]
[983]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
J, Sun SC, Wagner E, Wang Y, Xu Z, Zhou H, Resnick
L (2009) Synthesis and structure-activity relationship of a
novel series of heterocyclic sulfonamide gamma-secretase
inhibitors. Bioorg Med Chem 17, 4708-4717.
Hopkins CR (2012) ACS Chemical Neuroscience
molecule spotlight on Begacestat (GSI-953). ACS Chem
Neurosci 3, 3-4.
Anderson JJ, Holtz G, Baskin PP, Turner M, Rowe B,
Wang B, Kounnas MZ, Lamb BT, Barten D, Felsenstein K, McDonald I, Srinivasan K, Munoz B, Wagner
SL (2005) Reductions in beta-amyloid concentrations in
vivo by the gamma-secretase inhibitors BMS-289948 and
BMS-299897. Biochem Pharmacol 69, 689-698.
Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng
M, Munoz B, Srinivasan K, Wang B, Robertson BJ, Polson CT, Wang J, Roberts SB, Hendrick JP, Anderson JJ,
Loy JK, Denton R, Verdoorn TA, Smith DW, Felsenstein
KM (2005) Dynamics of {beta}-amyloid reductions in
brain, cerebrospinal fluid, and plasma of {beta}-amyloid
precursor protein transgenic mice treated with a {gamma}secretase inhibitor. J Pharmacol Exp Ther 312, 635643.
Zhang D, Hanson R, Roongta V, Dischino DD, Gao Q,
Sloan CP, Polson C, Keavy D, Zheng M, Mitroka J, Yeola
S (2006) In vitro and in vivo metabolism of a gammasecretase inhibitor BMS-299897 and generation of active
metabolites in milligram quantities with a microbial bioreactor. Curr Drug Metab 7, 883-896.
Zheng M, Wang J, Lubinski J, Flint OP, Krishna R, Yao M,
Pursley JM, Thakur A, Boulton DW, Santone KS, Barten
DM, Anderson JJ, Felsenstein KM, Hansel SB (2009)
Studies on the pharmacokinetics and metabolism of a
gamma-secretase inhibitor BMS-299897, and exploratory
investigation of CYP enzyme induction. Xenobiotica 39,
544-555.
Goldstein ME, Cao Y, Fiedler T, Toyn J, Iben L, Barten
DM, Pierdomenico M, Corsa J, Prasad CV, Olson RE, Li
YW, Zaczek R, Albright CF (2007) Ex vivo occupancy
of gamma-secretase inhibitors correlates with brain betaamyloid peptide reduction in Tg2576 mice. J Pharmacol
Exp Ther 323, 102-108.
Quinn K, Gullapalli RP, Merisko-Liversidge E, Goldbach E, Wong A, Liversidge GG, Hoffman W, Sauer
JM, Bullock J, Tonn G (2012) A formulation strategy
for gamma secretase inhibitor ELND006, a BCS class II
compound: Development of a nanosuspension formulation with improved oral bioavailability and reduced food
effects in dogs. J Pharm Sci 101, 1462-1474.
Quinn K, Gullapalli RP, Merisko-Liversidge E, Goldbach E, Wong A, Liversidge GG, Hoffman W, Sauer
JM, Bullock J, Tonn G (2012) A formulation strategy
for gamma secretase inhibitor ELND006, a BCS class II
compound: Development of a nanosuspension formulation with improved oral bioavailability and reduced food
effects in dogs. J Pharm Sci 101, 1462-1474.
Plentz R, Park JS, Rhim AD, Abravanel D, Hezel AF,
Sharma SV, Gurumurthy S, Deshpande V, Kenific C,
Settleman J, Majumder PK, Stanger BZ, Bardeesy N
(2009) Inhibition of gamma-secretase activity inhibits
tumor progression in a mouse model of pancreatic ductal
adenocarcinoma. Gastroenterology 136, 1741-1749.
Bai F, Tagen M, Colotta C, Miller L, Fouladi M, Stewart
CF (2010) Determination of the gamma-secretase inhibitor
MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS).
[984]
[985]
[986]
[987]
[988]
[989]
[990]
[991]
[992]
[993]
[994]
J Chromatogr B Analyt Technol Biomed Life Sci 878, 23482352.
Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL,
Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE,
Brown TM, Finley JE, Sokolowski SA, Hicks CD, Coffman KJ, Geoghegan KF, Brodney MA, Liston D, Tate B
(2010) Pharmacodynamics and pharmacokinetics of the
gamma-secretase inhibitor PF-3084014. J Pharmacol Exp
Ther 334, 269-277.
Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A,
Tsaparikos K, Jani JP, Hosea N, Sands M, Randolph S,
Smeal T (2010) Evaluation of selective gamma-secretase
inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.
Mol Cancer Ther 9, 1618-1628.
Brodney MA, Auperin DD, Becker SL, Bronk BS, Brown
TM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ,
Lanz TA, Liston D, Liu X, Martin BA, Nelson RB, Nolan
CE, Oborski CE, Parker CP, Richter KE, Pozdnyakov N,
Sahagan BG, Schachter JB, Sokolowski SA, Tate B, Van
Deusen JW, Wood DE, Wood KM (2011) Diamide aminoimidazoles: A novel series of gamma-secretase inhibitors
for the treatment of Alzheimer’s disease. Bioorg Med
Chem Lett 21, 2631-2636.
Samon JB, Castillo-Martin M, Hadler M, mbesi-Impiobato
A, Paietta E, Racevskis J, Wiernik PH, Rowe JM,
Jakubczak J, Randolph S, Cordon-Cardo C, Ferrando
AA (2012) Preclinical Analysis of the gamma-secretase
inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer
Ther 11, 1565-1575.
Peters JU, Galley G, Jacobsen H, Czech C, vid-Pierson
P, Kitas EA, Ozmen L (2007) Novel orally active,
dibenzazepinone-based gamma-secretase inhibitors.
Bioorg Med Chem Lett 17, 5918-5923.
Kitas EA, Galley G, Jakob-Roetne R, Flohr A, Wostl
W, Mauser H, Alker AM, Czech C, Ozmen L, vidPierson P, Reinhardt D, Jacobsen H (2008) Substituted
2-oxo-azepane derivatives are potent, orally active gammasecretase inhibitors. Bioorg Med Chem Lett 18, 304-308.
Hoffmann-Emery F, Jakob-Roetne R, Flohr A, Bliss F,
Reents R (2009) Improved synthesis of (S)-7-amino5H,7H-dibenzo[b,d]azepin-6-one, a bulding block for
g-secretase inhibitors. Tetrahedron Lett 50, 6380-6382.
Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H,
Linn M, Flohr A, Jakob-Rotne R, Jacobsen H, Glenn K,
Heimbrook D, Boylan JF (2009) Preclinical profile of a
potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
Cancer Res 69, 7672-7680.
He W, Luistro L, Carvajal D, Smith M, Nevins T, Yin X,
Cai J, Higgins B, Kolinsky K, Rizzo C, Packman K, Heimbrook D, Boylan JF (2011) High tumor levels of IL6 and
IL8 abrogate preclinical efficacy of the gamma-secretase
inhibitor, RO4929097. Mol Oncol 5, 292-301.
Wu J, Wiegand R, LoRusso P, Li J (2011) Validation
and implementation of a liquid chromatography/tandem
mass spectrometry assay for quantitation of the total and
unbound RO4929097, a gamma-secretase inhibitor targeting Notch signaling, in human plasma. J Chromatogr B
Analyt Technol Biomed Life Sci 879, 1537-1543.
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara
T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang
L, Higgins GA, Parker EM (2004) Chronic treatment with
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[995]
[996]
[997]
[998]
[999]
[1000]
[1001]
[1002]
[1003]
[1004]
[1005]
the gamma-secretase inhibitor LY-411,575 inhibits betaamyloid peptide production and alters lymphopoiesis and
intestinal cell differentiation. J Biol Chem 279, 1287612882.
Best JD, Jay MT, Otu F, Ma J, Nadin A, Ellis
S, Lewis HD, Pattison C, Reilly M, Harrison T,
Shearman MS, Williamson TL, Atack JR (2005)
Quantitative measurement of changes in amyloidbeta(40) in the rat brain and cerebrospinal fluid
following treatment with the gamma-secretase
inhibitor
LY-411575[N2-[(2S)-2-(3,5-difluorophenyl)2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-ox
o-6,7dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide].
J Pharmacol Exp Ther 313, 902-908.
Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite
J, Farlow M, Ness D, May PC (2005) Safety, tolerability,
and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin
Neuropharmacol 28, 126-132.
Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson
A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC
(2006) Effects of a gamma-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology
66, 602-604.
Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L,
Gonzales C, Farlow MR, May PC (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid
amyloid-beta after inhibition of gamma-secretase. Clin
Neuropharmacol 30, 317-325.
Hyde LA, McHugh NA, Chen J, Zhang Q, Manfra D,
Nomeir AA, Josien H, Bara T, Clader JW, Zhang L, Parker
EM, Higgins GA (2006) Studies to investigate the in vivo
therapeutic window of the gamma-secretase inhibitor
N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]N1-[(7S)-5-methyl-6-oxo -6,7-dihydro-5H-dibenzo[b,d]
azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8
mouse. J Pharmacol Exp Ther 319, 1133-1143.
Fauq AH, Simpson K, Maharvi GM, Golde T, Das P (2007)
A multigram chemical synthesis of the gamma-secretase
inhibitor LY411575 and its diastereoisomers. Bioorg Med
Chem Lett 17, 6392-6395.
Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM,
Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn
JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ (2008)
Phase 2 safety trial targeting amyloid beta production with
a gamma-secretase inhibitor in Alzheimer disease. Arch
Neurol 65, 1031-1038.
Bateman RJ, Siemers ER, Mawuenyega KG, Wen G,
Browning KR, Sigurdson WC, Yarasheski KE, Friedrich
SW, DeMattos RB, May PC, Paul SM, Holtzman DM
(2009) A gamma-secretase inhibitor decreases amyloidbeta production in the central nervous system. Ann Neurol
66, 48-54.
Henley DB, May PC, Dean RA, Siemers ER (2009)
Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of
Alzheimer’s disease. Expert Opin Pharmacother 10, 16571664.
Imbimbo BP, Peretto I (2009) Semagacestat, a gammasecretase inhibitor for the potential treatment of
Alzheimer’s disease. Curr Opin Investig Drugs 10, 721730.
Cummings J (2010) What can be inferred from the
interruption of the semagacestat trial for treatment
[1006]
[1007]
[1008]
[1009]
[1010]
[1011]
[1012]
[1013]
[1014]
[1015]
[1016]
[1017]
[1018]
[1019]
[1020]
[1021]
[1022]
[1023]
633
of Alzheimer’s disease? Biol Psychiatry 68, 876878.
Portelius E, Dean RA, Gustavsson MK, Andreasson U,
Zetterberg H, Siemers E, Blennow K (2010) A novel Abeta
isoform pattern in CSF reflects gamma-secretase inhibition
in Alzheimer disease. Alzheimers Res Ther 2, 7.
Yi P, Hadden C, Kulanthaivel P, Calvert N, Annes W,
Brown T, Barbuch RJ, Chaudhary A, yan-Oshodi MA,
Ring BJ (2010) Disposition and metabolism of semagacestat, a gamma-secretase inhibitor, in humans. Drug Metab
Dispos 38, 554-565.
Schor NF (2011) What the halted phase III gammasecretase inhibitor trial may (or may not) be telling us.
Ann Neurol 69, 237-239.
Willis BA, Zhang W, yan-Oshodi M, Lowe SL, Annes
WF, Sirois PJ, Friedrich S, de la PA (2012) Semagacestat
pharmacokinetics are not significantly affected by formulation, food, or time of dosing in healthy participants.
J Clin Pharmacol 52, 904-913.
Zhang W, Ayan-Oshodi M, Willis BA, Annes W, Hall SD,
Chiesa J, Seger M (2012) QT effect of semagacestat at therapeutic and supratherapeutic doses. Int J Clin Pharmacol
Ther 50, 290-299.
Wolfe MS (2006) The gamma-secretase complex:
Membrane-embedded proteolytic ensemble. Biochemistry
45, 7931-7939.
Aisen PS (2005) The development of anti-amyloid therapy for Alzheimer’s disease: From secretase modulators
to polymerisation inhibitors. CNS Drugs 19, 989-996.
Czirr E, Weggen S (2006) Gamma-secretase modulation
with Abeta42-lowering nonsteroidal anti-inflammatory
drugs and derived compounds. Neurodegener Dis 3, 298304.
Pissarnitski D (2007) Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel 10, 392-402.
Wolfe MS (2007) gamma-Secretase modulators. Curr
Alzheimer Res 4, 571-573.
Beher D (2008) Gamma-secretase modulation and its
promise for Alzheimer’s disease: A rationale for drug discovery. Curr Top Med Chem 8, 34-37.
Evin G (2008) Gamma-secretase modulators: Hopes and
setbacks for the future of Alzheimer’s treatment. Expert
Rev Neurother 8, 1611-1613.
Peretto I, La Porta E (2008) Gamma-secretase modulation and its promise for Alzheimer’s disease: A medicinal
chemistry perspective. Curr Top Med Chem 8, 38-46.
Yang T, Arslanova D, Gu Y, Augelli-Szafran C, Xia W
(2008) Quantification of gamma-secretase modulation differentiates inhibitor compound selectivity between two
substrates Notch and amyloid precursor protein. Mol Brain
1, 15.
Bulic B, Ness J, Hahn S, Rennhack A, Jumpertz T, Weggen
S (2011) Chemical biology, molecular mechanism and
clinical perspective of gamma-secretase modulators in
Alzheimer’s disease. Curr Neuropharmacol 9, 598-622.
Pettersson M, Kauffman GW, am Ende CW, Patel NC, Stiff
C, Tran TP, Johnson DS (2011) Novel gamma-secretase
modulators: A review of patents from 2008 to 2010. Expert
Opin Ther Pat 21, 205-226.
Jumpertz T, Rennhack A, Ness J, Baches S, Pietrzik CU,
Bulic B, Weggen S (2012) Presenilin is the molecular target
of acidic gamma-secretase modulators in living cells. PLoS
One 7, e30484.
Wagner SL, Tanzi RE, Mobley WC, Galasko D (2012)
Potential use of gamma-secretase modulators in the
634
[1024]
[1025]
[1026]
[1027]
[1028]
[1029]
[1030]
[1031]
[1032]
[1033]
[1034]
[1035]
[1036]
[1037]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
treatment of Alzheimer disease. Arch Neurol, doi:
10.1001/archneurol.2012.540
Xia W, Wong ST, Hanlon E, Morin P (2012) gammasecretase modulator in Alzheimer’s disease: Shifting the
end. J Alzheimers Dis 31, 685-696.
Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH,
Golde TE (2003) NSAIDs and enantiomers of flurbiprofen
target gamma-secretase and lower Abeta 42 in vivo. J Clin
Invest 112, 440-449.
Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V,
Fauq A, Golde TE, Koo EH (2003) Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta
42 production by direct modulation of gamma-secretase
activity. J Biol Chem 278, 31831-31837.
Peretto I, Radaelli S, Parini C, Zandi M, Raveglia LF,
Dondio G, Fontanella L, Misiano P, Bigogno C, Rizzi A,
Riccardi B, Biscaioli M, Marchetti S, Puccini P, Catinella
S, Rondelli I, Cenacchi V, Bolzoni PT, Caruso P, Villetti
G, Facchinetti F, Del GE, Moretto N, Imbimbo BP (2005)
Synthesis and biological activity of flurbiprofen analogues
as selective inhibitors of beta-amyloid(1)(-)(42) secretion.
J Med Chem 48, 5705-5720.
Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP,
Koo EH, Golde TE, Nicolle MM (2007) Chronic administration of R-flurbiprofen attenuates learning impairments
in transgenic amyloid precursor protein mice. BMC Neurosci 8, 54.
Zhao X, Rebeck GW, Hoe HS, Andrews PM (2008) Tarenflurbil protection from cytotoxicity is associated with an
upregulation of neurotrophins. J Alzheimers Dis 15, 397407.
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb
EA, Laughlin MA (2008) Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: A randomised
phase II trial. Lancet Neurol 7, 483-493.
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock
G, Swabb EA, Zavitz KH (2009) Effect of tarenflurbil on
cognitive decline and activities of daily living in patients
with mild Alzheimer disease: A randomized controlled
trial. JAMA 302, 2557-2564.
Imbimbo BP (2009) Why did tarenflurbil fail in
Alzheimer’s disease? J Alzheimers Dis 17, 757-760.
Sano M (2010) Tarenflurbil: Mechanisms and myths. Arch
Neurol 67, 750-752.
Vellas B (2010) Tarenflurbil for Alzheimer’s disease:
A “shot on goal” that missed. Lancet Neurol 9, 235237.
Imbimbo BP, Del GE, Cenacchi V, Volta R, Villetti G,
Facchinetti F, Riccardi B, Puccini P, Moretto N, Grassi F,
Ottonello S, Leon A (2007) In vitro and in vivo profiling of
CHF5022 and CHF5074 Two beta-amyloid1-42 lowering
agents. Pharmacol Res 55, 318-328.
Imbimbo BP, Del GE, Colavito D, D’Arrigo A, Dalle CM,
Villetti G, Facchinetti F, Volta R, Pietrini V, Baroc MF,
Serneels L, De SB, Leon A (2007) 1-(3 ,4 -Dichloro-2fluoro[1,1 -biphenyl]-4-yl)-cyclopropanecarboxylic acid
(CHF5074), a novel gamma-secretase modulator, reduces
brain beta-amyloid pathology in a transgenic mouse model
of Alzheimer’s disease without causing peripheral toxicity.
J Pharmacol Exp Ther 323, 822-830.
Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F,
Cenacchi V, Volta R, Lanzillotta A, Pizzi M, Windisch
M (2009) CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning
[1038]
[1039]
[1040]
[1041]
[1042]
[1043]
[1044]
[1045]
[1046]
[1047]
deficit in a mouse model of Alzheimer’s disease. Br J
Pharmacol 156, 982-993.
Imbimbo BP, Giardino L, Sivilia S, Giuliani A, Gusciglio
M, Pietrini V, Del GE, D’Arrigo A, Leon A, Villetti G,
Calza L (2010) CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and
reverses contextual memory deficit in a transgenic mouse
model of Alzheimer’s disease. J Alzheimers Dis 20, 159173.
Lanzillotta A, Sarnico I, Benarese M, Branca C, Baiguera
C, Hutter-Paier B, Windisch M, Spano P, Imbimbo BP,
Pizzi M (2011) The gamma-secretase modulator CHF5074
reduces the accumulation of native hyperphosphorylated
tau in a transgenic mouse model of Alzheimer’s disease.
J Mol Neurosci 45, 22-31.
Balducci C, Mehdawy B, Mare L, Giuliani A, Lorenzini
L, Sivilia S, Giardino L, Calza L, Lanzillotta A, Sarnico I,
Pizzi M, Usiello A, Viscomi AR, Ottonello S, Villetti G,
Imbimbo BP, Nistico G, Forloni G, Nistico R (2011) The
gamma-secretase modulator CHF5074 restores memory
and hippocampal synaptic plasticity in plaque-free Tg2576
mice. J Alzheimers Dis 24, 799-816.
Poli G, Corda E, Lucchini B, Puricelli M, Martino PA,
Dall’ara P, Villetti G, Bareggi SR, Corona C, Costassa
EV, Gazzuola P, Iulini B, Mazza M, Acutis P, Mantegazza
P, Casalone C, Imbimbo BP (2012) Therapeutic effect of
CHF5074, a new gamma-secretase modulator, in a mouse
model of scrapie. Prion 6, 62-72.
Tian G, Sobotka-Briner CD, Zysk J, Liu X, Birr C,
Sylvester MA, Edwards PD, Scott CD, Greenberg BD
(2002) Linear non-competitive inhibition of solubilized
human gamma-secretase by pepstatin A methylester,
L685458, sulfonamides, and benzodiazepines. J Biol
Chem 277, 31499-31505.
Tian G, Ghanekar SV, Aharony D, Shenvi AB, Jacobs RT,
Liu X, Greenberg BD (2003) The mechanism of gammasecretase: Multiple inhibitor binding sites for transition
state analogs and small molecule inhibitors. J Biol Chem
278, 28968-28975.
Borgegard T, Jureus A, Olsson F, Rosqvist S, Sabirsh
A, Rotticci D, Paulsen K, Klintenberg R, Yan H, Waldman M, Stromberg K, Nord J, Johansson J, Regner A,
Parpal S, Malinowsky D, Radesater AC, Li T, Singh R,
Eriksson H, Lundkvist J (2012) First and second generation gamma-secretase modulators (GSMs) modulate
amyloid-beta (Abeta) peptide production through different
mechanisms. J Biol Chem 287, 11810-11819.
Sehgelmeble F, Janson J, Ray C, Rosqvist S, Gustavsson S,
Nilsson LI, Minidis A, Holenz J, Rotticci D, Lundkvist J,
Arvidsson PI (2012) Sulfonimidamides as sulfonamides
bioisosteres: Rational evaluation through synthetic, in
vitro, and in vivo studies with gamma-secretase inhibitors.
ChemMedChem 7, 396-399.
Wanngren J, Ottervald J, Parpal S, Portelius E, Stromberg
K, Borgegard T, Klintenberg R, Jureus A, Blomqvist
J, Blennow K, Zetterberg H, Lundkvist J, Rosqvist
S, Karlstrom H (2012) Second generation gammasecretase modulators exhibit different modulation of Notch
beta and Abeta production. J Biol Chem 287, 3264032650.
Peng HR, Talreja T, Xin ZL, Cuergvo JH, Kumaravek G,
Humora MJ, Xu L, Rohde E, Gan L, Jung MY, Sahckett
MN, Chollate S, Dunah AW, Snodgrass-belt PA, Arnold
HM, Taveras AG, Rhodes KJ, Scannevin RH (2011)
Discovery of BIIB042, a potent, selective, and orally
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1048]
[1049]
[1050]
[1051]
[1052]
[1053]
[1054]
[1055]
[1056]
[1057]
[1058]
bioavailable gamma-secretase modulator. ACS Med Chem
Lett 2, 786-791.
Xin Z, Peng H, Zhang A, Talreja T, Kumaravel G, Xu
L, Rohde E, Jung MY, Shackett MN, Kocisko D, Chollate S, Dunah AW, Snodgrass-Belt PA, Arnold HM,
Taveras AG, Rhodes KJ, Scannevin RH (2011) Discovery
of 4-aminomethylphenylacetic acids as gamma-secretase
modulators via a scaffold design approach. Bioorg Med
Chem Lett 21, 7277-7280.
Garcia Y, Hannam JC, Harrison T, Hamblett CL HJKJ,
Madin A, Ridgill MP, Seward E (2007) Piperidines and
related compounds for treatment of Alzheimer’s disease.
WO/2007-125364. Prior. 26.04.2006 for Merck Sharp &
Dohme Ltd. UK.
Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H,
Shitaka Y, Ni K, Matsuoka N (2012) Differential effects
between gamma-secretase inhibitors and modulators
on cognitive function in amyloid precursor proteintransgenic and nontransgenic mice. J Neurosci 32, 20372050.
Hall A, Elliott RL, Giblin GM, Hussain I, Musgrave J,
Naylor A, Sasse R, Smith B (2010) Piperidine-derived
gamma-secretase modulators. Bioorg Med Chem Lett 20,
1306-1311.
Hussain I, Harrison DC, Hawkins J, Chapman T, Marshall I, Facci L, Ahmed S, Brackenborough K, Skaper
SD, Mead TL, Smith BB, Giblin GM, Hall A, Gonzalez MI, Richardson JC (2011) TASTPM mice expressing
amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to gamma-secretase modulation and
amyloid-beta lowering by GSM-10h. Neurodegener Dis
8, 15-24.
Hawkins J, Harrison DC, Ahmed S, Davis RP, Chapman
T, Marshall I, Smith B, Mead TL, Medhurst A, Giblin
GM, Hall A, Gonzalez MI, Richardson J, Hussain I (2011)
Dynamics of Abeta42 reduction in plasma, CSF and brain
of rats treated with the gamma-secretase modulator, GSM10h. Neurodegener Dis 8, 455-464.
Li T, Huang Y, Jin S, Ye L, Rong N, Yang X, Ding Y, Cheng
Z, Zhang J, Wan Z, Harrison DC, Hussain I, Hall A, Lee
DH, Lau LF, Matsuoka Y (2012) Gamma-secretase modulators do not induce Abeta-rebound and accumulation of
beta-C-terminal fragment. J Neurochem 121, 277-286.
Wan Z, Hall A, Jin Y, Xiang JN, Yang E, Eatherton A,
Smith B, Yang G, Yu H, Wang J, Ye L, Lau LF, Yang
T, Mitchell W, Cai W, Zhang X, Sang Y, Wang Y, Tong
Z, Cheng Z, Hussain I, Elliott JD, Matsuoka Y (2011)
Pyridazine-derived gamma-secretase modulators. Bioorg
Med Chem Lett 21, 4016-4019.
Wan Z, Hall A, Sang Y, Xiang JN, Yang E, Smith B, Harrison DC, Yang G, Yu H, Price HS, Wang J, Hawkins J,
Lau LF, Johnson MR, Li T, Zhao W, Mitchell WL, Su X,
Zhang X, Zhou Y, Jin Y, Tong Z, Cheng Z, Hussain I, Elliott
JD, Matsuoka Y (2011) Pyridine-derived gamma-secretase
modulators. Bioorg Med Chem Lett 21, 4832-4835.
Bischoff F, Berthelot D, De Cleyn M, Macdonald G, Minne
G, Oehlrich D, Pieters S, Surkyn M, Trabanco AA, Tresadern G, Van Brandt S, Velter I, Zaja M, Borghys H,
Masungi C, Mercken M, Gijsen HJ (2012) Design and
synthesis of a novel series of bicyclic heterocycles as
potent gamma-secretase modulators. J Med Chem, doi:
10.1021/jm201710f [Epubl ahead of print].
Caldwell JP, Bennett CE, McCracken TM, Mazzola RD,
Bara T, Buevich A, Burnett DA, Chu I, Cohen-Williams M,
Josein H, Hyde L, Lee J, McKittrick B, Song L, Terracina
[1059]
[1060]
[1061]
[1062]
[1063]
[1064]
[1065]
[1066]
[1067]
[1068]
635
G, Voigt J, Zhang L, Zhu Z (2010) Iminoheterocycles as
gamma-secretase modulators. Bioorg Med Chem Lett 20,
5380-5384.
Rivkin A, Ahearn SP, Chichetti SM, Kim YR, Li C, Rosenau A, Kattar SD, Jung J, Shah S, Hughes BL, Crispino
JL, Middleton RE, Szewczak AA, Munoz B, Shearman
MS (2010) Piperazinyl pyrimidine derivatives as potent
gamma-secretase modulators. Bioorg Med Chem Lett 20,
1269-1271.
Rivkin A, Ahearn SP, Chichetti SM, Hamblett CL, Garcia Y, Martinez M, Hubbs JL, Reutershan MH, Daniels
MH, Siliphaivanh P, Otte KM, Li C, Rosenau A, Surdi
LM, Jung J, Hughes BL, Crispino JL, Nikov GN, Middleton RE, Moxham CM, Szewczak AA, Shah S, Moy LY,
Kenific CM, Tanga F, Cruz JC, Andrade P, Angagaw MH,
Shomer NH, Miller T, Munoz B, Shearman MS (2010)
Purine derivatives as potent gamma-secretase modulators.
Bioorg Med Chem Lett 20, 2279-2282.
Stanton MG, Hubbs J, Sloman D, Hamblett C, Andrade P,
Angagaw M, Bi G, Black RM, Crispino J, Cruz JC, Fan E,
Farris G, Hughes BL, Kenific CM, Middleton RE, Nikov
G, Sajonz P, Shah S, Shomer N, Szewczak AA, Tanga F,
Tudge MT, Shearman M, Munoz B (2010) Fluorinated
piperidine acetic acids as gamma-secretase modulators.
Bioorg Med Chem Lett 20, 755-758.
Fischer C, Shah S, Hughes BL, Nikov GN, Crispino JL,
Middleton RE, Szewczak AA, Munoz B, Shearman MS
(2011) Quinazolinones as gamma-secretase modulators.
Bioorg Med Chem Lett 21, 773-776.
Qin J, Dhondi P, Huang X, Mandal M, Zhao Z, Pissarnitski
D, Zhou W, Aslanian R, Zhu Z, Greenlee W, Clader J,
Zhang L, Cohen-Williams M, Jones N, Hyde L, Palani
A (2011) Discovery of fused 5,6-bicyclic heterocycles as
gamma-secretase modulators. Bioorg Med Chem Lett 21,
664-669.
Beher D, Clarke EE, Wrigley JD, Martin AC, Nadin
A, Churcher I, Shearman MS (2004) Selected nonsteroidal anti-inflammatory drugs and their derivatives
target gamma-secretase at a novel site. Evidence for
an allosteric mechanism. J Biol Chem 279, 4341943426.
Fischer C, Zultanski SL, Zhou H, Methot JL, Brown WC,
Mampreian DM, Schell AJ, Shah S, Nuthall H, Hughes BL,
Smotrov N, Kenific CM, Cruz JC, Walker D, Bouthillette
M, Nikov GN, Savage DF, Jeliazkova-Mecheva VV, Diaz
D, Szewczak AA, Bays N, Middleton RE, Munoz B, Shearman MS (2011) Triazoles as gamma-secretase modulators.
Bioorg Med Chem Lett 21, 4083-4087.
Fischer C, Zultanski SL, Zhou H, Methot JL, Shah S,
Nuthall H, Hughes BL, Smotrov N, Hill A, Szewczak
AA, Moxham CM, Bays N, Middleton RE, Munoz B,
Shearman MS (2012) Triazoloamides as potent gammasecretase modulators with reduced hERG liability. Bioorg
Med Chem Lett 22, 3140-3146.
Huang X, Aslanian R, Zhou W, Zhu X, Qin J, Greenlee
W, Zhu Z, Zhang L, Hyde L, Chu I, Coen-Willaims M,
Palani A (2010) The discovery of pyridone and pyridazone
heterocycles as gamma-secretase modulators. ACS Med
Chem Lett 1, 184-187.
Pettersson M, Johnson DS, Subramanyam C, Bales KR,
am Ende CW, Fish BA, Green ME, Kauffman GW, Lira
R, Mullins PB, Navaratnam T, Sakya SM, Stiff CM, Tran
TP, Vetelino BC, Xie L, Zhang L, Pustilnik LR, Wood KM,
O’Donnell CJ (2012) Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active
636
[1069]
[1070]
[1071]
[1072]
[1073]
[1074]
[1075]
[1076]
[1077]
[1078]
[1079]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
gamma-secretase modulators. Bioorg Med Chem Lett 22,
2906-2911.
Kounnas MZ, Danks AM, Cheng S, Tyree C, Ackerman
E, Zhang X, Ahn K, Nguyen P, Comer D, Mao L, Yu
C, Pleynet D, Digregorio PJ, Velicelebi G, Stauderman
KA, Comer WT, Mobley WC, Li YM, Sisodia SS, Tanzi
RE, Wagner SL (2010) Modulation of gamma-secretase
reduces beta-amyloid deposition in a transgenic mouse
model of Alzheimer’s disease. Neuron 67, 769-780.
Narlawar R, Perez Revuelta BI, Haass C, Steiner
H, Schmidt B, Baumann K (2006) Scaffold of the
cyclooxygenase-2 (COX-2) inhibitor carprofen provides
Alzheimer gamma-secretase modulators. J Med Chem 49,
7588-7591.
Narlawar R, Perez Revuelta BI, Baumann K, Schubenel
R, Haass C, Steiner H, Schmidt B (2007) N-Substituted
carbazolyloxyacetic acids modulate Alzheimer associated
gamma-secretase. Bioorg Med Chem Lett 17, 176-182.
Narlawar R, Baumann K, Czech C, Schmidt B (2007) Conversion of the LXR-agonist TO-901317–from inverse to
normal modulation of gamma-secretase by addition of a
carboxylic acid and a lipophilic anchor. Bioorg Med Chem
Lett 17, 5428-5431.
Baumann S, Hottecke N, Schubenel R, Baumann K,
Schmidt B (2009) NSAID-derived gamma-secretase modulators. Part III: Membrane anchoring. Bioorg Med Chem
Lett 19, 6986-6990.
Zall A, Kieser D, Hottecke N, Naumann EC,
Thomaszewski B, Schneider K, Steinbacher DT,
Schubenel R, Masur S, Baumann K, Schmidt B (2011)
NSAID-derived gamma-secretase modulation requires
an acidic moiety on the carbazole scaffold. Bioorg Med
Chem 19, 4903-4909.
Hahn S, Bruning T, Ness J, Czirr E, Baches S, Gijsen
H, Korth C, Pietrzik CU, Bulic B, Weggen S (2011)
Presenilin-1 but not amyloid precursor protein mutations
present in mouse models of Alzheimer’s disease attenuate
the response of cultured cells to gamma-secretase modulators regardless of their potency and structure. J Neurochem
116, 385-395.
Kukar TL, Ladd TB, Robertson P, Pintchovski SA, Moore
B, Bann MA, Ren Z, Jansen-West K, Malphrus K, Eggert
S, Maruyama H, Cottrell BA, Das P, Basi GS, Koo EH,
Golde TE (2011) Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid beta peptide
length: Support for a sequential model of gamma-secretase
intramembrane proteolysis and regulation by the amyloid
beta precursor protein (APP) juxtamembrane region. J Biol
Chem 286, 39804-39812.
Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar
R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price
RW, Moore B, Rangachari V, Cusack B, Eriksen J, JansenWest K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi
S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe
MS, Schmidt B, Walsh DM, Koo EH, Golde TE (2008)
Substrate-targeting gamma-secretase modulators. Nature
453, 925-929.
Crump CJ, Johnson DS, Li YM (2011) Target of gammasecretase modulators, presenilin marks the spot. EMBO J
30, 4696-4698.
Crump CJ, Fish BA, Castro SV, Chau DM, Gertsik N, Ahn
K, Stiff C, Pozdnyakov N, Bales KR, Johnson DS, Li YM
(2011) Piperidine acetic acid based gamma-secretase modulators directly bind to Presenilin-1. ACS Chem Neurosci
2, 705-710.
[1080]
[1081]
[1082]
[1083]
[1084]
[1085]
[1086]
[1087]
[1088]
[1089]
[1090]
[1091]
[1092]
Crump CJ, am Ende CW, Ballard TE, Pozdnyakov N, Pettersson M, Chau DM, Bales KR, Li YM, Johnson DS
(2012) Development of clickable active site-directed photoaffinity probes for gamma-secretase. Bioorg Med Chem
Lett 22, 2997-3000.
Ebke A, Luebbers T, Fukumori A, Shirotani K, Haass C,
Baumann K, Steiner H (2011) Novel gamma-secretase
enzyme modulators directly target presenilin protein.
J Biol Chem 286, 37181-37186.
Kretner B, Fukumori A, Gutsmiedl A, Page RM, Luebbers
T, Galley G, Baumann K, Haass C, Steiner H (2011) Attenuated Abeta42 responses to low potency gamma-secretase
modulators can be overcome for many pathogenic presenilin mutants by second-generation compounds. J Biol
Chem 286, 15240-15251.
Ohki Y, Higo T, Uemura K, Shimada N, Osawa S, Berezovska O, Yokoshima S, Fukuyama T, Tomita T, Iwatsubo
T (2011) Phenylpiperidine-type gamma-secretase modulators target the transmembrane domain 1 of presenilin 1.
EMBO J 30, 4815-4824.
Zettl H, Ness J, Hahnke V, Beher D, Jumpertz T,
Saric A, Baumann K, Pietrzik CU, Bulic B, Schneider G, Weggen S (2012) Discovery of gamma-secretase
modulators with a novel activity profile by textbased virtual screening. ACS Chem Biol 7, 14881495.
Uemura K, Lill CM, Li X, Peters JA, Ivanov A, Fan
Z, DeStrooper B, Bacskai BJ, Hyman BT, Berezovska
O (2009) Allosteric modulation of PS1/gamma-secretase
conformation correlates with amyloid beta(42/40) ratio.
PLoS One 4, e7893.
Uemura K, Farner KC, Hashimoto T, Nasser-Ghodsi N,
Wolfe MS, Koo EH, Hyman BT, Berezovska O (2010)
Substrate docking to gamma-secretase allows access of
gamma-secretase modulators to an allosteric site. Nat
Commun 1, 130.
Uemura K, Farner KC, Nasser-Ghodsi N, Jones P, Berezovska O (2011) Reciprocal relationship between APP
positioning relative to the membrane and PS1 conformation. Mol Neurodegener 6, 15.
Barrett PJ, Sanders CR, Kaufman SA, Michelsen K, Jordan
JB (2011) NSAID-based gamma-secretase modulators do
not bind to the amyloid-beta polypeptide. Biochemistry 50,
10328-10342.
Hieke M, Ness J, Steri R, Dittrich M, Greiner C,
Werz O, Baumann K, Schubert-Zsilavecz M, Weggen
S, Zettl H (2010) Design, synthesis, and biological
evaluation of a novel class of gamma-secretase modulators with PPARgamma activity. J Med Chem 53, 46914700.
Hieke M, Ness J, Steri R, Greiner C, Werz O, SchubertZsilavecz M, Weggen S, Zettl H (2011) SAR studies
of acidic dual gamma-secretase/PPARgamma modulators.
Bioorg Med Chem 19, 5372-5382.
Van Broeck B, Chen JM, Treton G, Desmidt M, Hopf
C, Ramsden N, Karran E, Mercken M, Rowley A (2011)
Chronic treatment with a novel gamma-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in
a mouse model of Alzheimer’s disease. Br J Pharmacol
163, 375-389.
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J,
Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (2010) Gamma-secretase activating protein is a
therapeutic target for Alzheimer’s disease. Nature 467,
95-98.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1093]
[1094]
[1095]
[1096]
[1097]
[1098]
[1099]
[1100]
[1101]
[1102]
[1103]
[1104]
[1105]
[1106]
St George-Hyslop P, Schmitt-Ulms G (2010) Alzheimer’s
disease: Selectively tuning gamma-secretase. Nature 467,
36-37.
Satoh J, Tabunoki H, Ishida T, Saito Y, Arima K
(2012) Immunohistochemical characterization of gammasecretase activating protein expression in Alzheimer’s
disease brains. Neuropathol Appl Neurobiol 38, 132-141.
Deatherage CL, Hadziselimovic A, Sanders CR (2012)
Purification and characterization of the human gammasecretase activating protein. Biochemistry 51, 5153-5159.
Gulinello M, Chen F, Dobrenis K (2008) Early deficits in
motor coordination and cognitive dysfunction in a mouse
model of the neurodegenerative lysosomal storage disorder, Sandhoff disease. Behav Brain Res 193, 315-319.
Chapman KE, Seckl JR (2008) 11beta-HSD1, inflammation, metabolic disease and age-related cognitive
(dys)function. Neurochem Res 33, 624-636.
Maclullich AM, Ferguson KJ, Reid LM, Deary IJ,
Starr JM, Wardlaw JM, Walker BR, Andrew R, Seckl
JR (2012) 11beta-hydroxysteroid dehydrogenase type 1,
brain atrophy and cognitive decline. Neurobiol Aging 33,
207-208.
Holmes MC, Carter RN, Noble J, Chitnis S, Dutia
A, Paterson JM, Mullins JJ, Seckl JR, Yau JL (2010)
11beta-hydroxysteroid dehydrogenase type 1 expression
is increased in the aged mouse hippocampus and parietal
cortex and causes memory impairments. J Neurosci 30,
6916-6920.
Yau JL, McNair KM, Noble J, Brownstein D, Hibberd C,
Morton N, Mullins JJ, Morris RG, Cobb S, Seckl JR (2007)
Enhanced hippocampal long-term potentiation and spatial learning in aged 11beta-hydroxysteroid dehydrogenase
type 1 knock-out mice. J Neurosci 27, 10487-10496.
Yau JL, Noble J, Seckl JR (2011) 11beta-hydroxysteroid
dehydrogenase type 1 deficiency prevents memory deficits
with aging by switching from glucocorticoid receptor
to mineralocorticoid receptor-mediated cognitive control.
J Neurosci 31, 4188-4193.
Sooy K, Webster SP, Noble J, Binnie M, Walker BR,
Seckl JR, Yau JL (2010) Partial deficiency or short-term
inhibition of 11beta-hydroxysteroid dehydrogenase type 1
improves cognitive function in aging mice. J Neurosci 30,
13867-13872.
Mohler EG, Browman KE, Roderwald VA, Cronin EA,
Markosyan S, Scott BR, Strakhova MI, Drescher KU,
Hornberger W, Rohde JJ, Brune ME, Jacobson PB, Rueter
LE (2011) Acute inhibition of 11beta-hydroxysteroid
dehydrogenase type-1 improves memory in rodent models
of cognition. J Neurosci 31, 5406-5413.
Sandeep TC, Yau JL, MacLullich AM, Noble J, Deary
IJ, Walker BR, Seckl JR (2004) 11Beta-hydroxysteroid
dehydrogenase inhibition improves cognitive function in
healthy elderly men and type 2 diabetics. Proc Natl Acad
Sci U S A 101, 6734-6739.
Webster SP, Binnie M, McConnell KM, Sooy K, Ward
P, Greaney MF, Vinter A, Pallin TD, Dyke HJ, Gill MI,
Warner I, Seckl JR, Walker BR (2010) Modulation of
11beta-hydroxysteroid dehydrogenase type 1 activity by
1,5-substituted 1H-tetrazoles. Bioorg Med Chem Lett 20,
3265-3271.
Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T,
Maeda J, Ji B, Ono M, Staufenbiel M, Suhara T, Saido TC
(2012) Mechanistic involvement of the calpain-calpastatin
system in Alzheimer neuropathology. FASEB J 26, 12041217.
[1107]
[1108]
[1109]
[1110]
[1111]
[1112]
[1113]
[1114]
[1115]
[1116]
[1117]
[1118]
[1119]
[1120]
637
Battaglia F, Trinchese F, Liu S, Walter S, Nixon RA,
Arancio O (2003) Calpain inhibitors, a treatment for
Alzheimer’s disease: Position paper. J Mol Neurosci 20,
357-362.
Getz GS (2012) Calpain inhibition as a potential treatment
of Alzheimer’s disease. Am J Pathol 181, 388-391.
Liang Z, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2007)
Down-regulation of cAMP-dependent protein kinase by
over-activated calpain in Alzheimer disease brain. J Neurochem 103, 2462-2470.
Morales-Corraliza J, Berger JD, Mazzella MJ, Veeranna,
Neubert TA, Ghiso J, Rao MV, Staufenbiel M, Nixon
RA, Mathews PM (2012) Calpastatin modulates APP processing in the brains of beta-amyloid depositing but not
wild-type mice. Neurobiol Aging 33, 1125-1128.
Neuhof C, Fabiunke V, Deibele K, Speth M, Moller
A, Lubisch W, Fritz H, Tillmanns H, Neuhof H (2004)
Reduction of myocardial infarction by calpain inhibitors
A-705239 and A-705253 in isolated perfused rabbit hearts.
Biol Chem 385, 1077-1082.
Neuhof C, Fabiunk V, Speth M, Moller A, Fritz F, Tillmanns H, Neuhof H, Erdogan A (2008) Reduction of
myocardial infarction by postischemic administration of
the calpain inhibitor A-705253 in comparison to the
Na(+)/H(+) exchange inhibitor Cariporide in isolated perfused rabbit hearts. Biol Chem 389, 1505-1512.
Nangle MR, Cotter MA, Cameron NE (2006) The calpain inhibitor, A-705253, corrects penile nitrergic nerve
dysfunction in diabetic mice. Eur J Pharmacol 538, 148153.
Nimmrich V, Szabo R, Nyakas C, Granic I, Reymann
KG, Schroder UH, Gross G, Schoemaker H, Wicke K,
Moller A, Luiten P (2008) Inhibition of calpain prevents Nmethyl-D-aspartate-induced degeneration of the nucleus
basalis and associated behavioral dysfunction. J Pharmacol Exp Ther 327, 343-352.
Nimmrich V, Reymann KG, Strassburger M, Schoder UH,
Gross G, Hahn A, Schoemaker H, Wicke K, Moller A
(2010) Inhibition of calpain prevents NMDA-induced cell
death and beta-amyloid-induced synaptic dysfunction in
hippocampal slice cultures. Br J Pharmacol 159, 15231531.
Sinjoanu RC, Kleinschmidt S, Bitner RS, Brioni JD,
Moeller A, Ferreira A (2008) The novel calpain inhibitor
A-705253 potently inhibits oligomeric beta-amyloidinduced dynamin 1 and tau cleavage in hippocampal
neurons. Neurochem Int 53, 79-88.
Granic I, Nyakas C, Luiten PG, Eisel UL, Halmy LG,
Gross G, Schoemaker H, Moller A, Nimmrich V (2010)
Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in
rats. Neuropharmacology 59, 334-342.
Nikkel AL, Martino B, Markosyan S, Brederson JD,
Medeiros R, Moeller A, Bitner RS (2012) The novel
calpain inhibitor A-705253 prevents stress-induced tau
hyperphosphorylation in vitro and in vivo. Neuropharmacology 63, 606-612.
Medeiros R, Kitazawa M, Chabrier MA, Cheng D,
Baglietto-Vargas D, Kling A, Moeller A, Green KN,
Laferla FM (2012) Calpain inhibitor A-705253 mitigates Alzheimer’s disease-like pathology and cognitive
decline in aged 3xTgAD mice. Am J Pathol 181, 616625.
Saatman KE, Murai H, Bartus RT, Smith DH, Hayward NJ,
Perri BR, McIntosh TK (1996) Calpain inhibitor AK295
638
[1121]
[1122]
[1123]
[1124]
[1125]
[1126]
[1127]
[1128]
[1129]
[1130]
[1131]
[1132]
[1133]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
attenuates motor and cognitive deficits following experimental brain injury in the rat. Proc Natl Acad Sci U S A
93, 3428-3433.
Oka T, Walkup RD, Tamada Y, Nakajima E, Tochigi
A, Shearer TR, Azuma M (2006) Amelioration of
retinal degeneration and proteolysis in acute ocular hypertensive rats by calpain inhibitor ((1S)-1((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)
amino)carbonyl)-3-me thylbutyl)carbamic acid 5methoxy-3-oxapentyl ester. Neuroscience 141, 21392145.
Shimazawa M, Suemori S, Inokuchi Y, Matsunaga
N, Nakajima Y, Oka T, Yamamoto T, Hara H
(2010) A novel calpain inhibitor, ((1S)-1-((((1S)1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)
carbonyl)-3-me thylbutyl)carbamic acid 5-methoxy-3oxapentyl ester (SNJ-1945), reduces murine retinal cell
death in vitro and in vivo. J Pharmacol Exp Ther 332,
380-387.
Koumura A, Nonaka Y, Hyakkoku K, Oka T, Shimazawa
M, Hozumi I, Inuzuka T, Hara H (2008) A novel calpain
inhibitor, ((1S)-1((((1S)-1-benzyl-3-cyclopropylamino2,3-di-oxopropyl)amino)carbonyl)-3-met
hylbutyl)
carbamic acid 5-methoxy-3-oxapentyl ester, protects
neuronal cells from cerebral ischemia-induced damage in
mice. Neuroscience 157, 309-318.
Shirasaki Y, Yamaguchi M, Miyashita H (2006) Retinal
penetration of calpain inhibitors in rats after oral administration. J Ocul Pharmacol Ther 22, 417-424.
Shirasaki Y, Nakamura M, Yamaguchi M, Miyashita H,
Sakai O, Inoue J (2006) Exploration of orally available
calpain inhibitors 2: Peptidyl hemiacetal derivatives. J Med
Chem 49, 3926-3932.
Shirasaki Y, Miyashita H, Yamaguchi M (2006) Exploration of orally available calpain inhibitors. Part 3:
Dipeptidyl alpha-ketoamide derivatives containing pyridine moiety. Bioorg Med Chem 14, 5691-5698.
Shirasaki Y, Miyashita H, Yamaguchi M, Inoue J,
Nakamura M (2005) Exploration of orally available calpain inhibitors: Peptidyl alpha-ketoamides containing an
amphiphile at P3 site. Bioorg Med Chem 13, 44734484.
Shirasaki Y, Takahashi H, Yamaguchi M, Inoue J (2008)
Molecular design to enhance the penetration into the retina
via ocular instillation. Bioorg Med Chem Lett 18, 51745177.
Ennes-Vidal V, Menna-Barreto RF, Santos AL, Branquinha MH, vila-Levy CM (2010) Effects of the calpain
inhibitor MDL28170 on the clinically relevant forms of
Trypanosoma cruzi in vitro. J Antimicrob Chemother 65,
1395-1398.
Ennes-Vidal V, Menna-Barreto RF, Santos AL, Branquinha MH, vila-Levy CM (2011) MDL28170, a calpain
inhibitor, affects Trypanosoma cruzi metacyclogenesis, ultrastructure and attachment to Rhodnius prolixus
midgut. PLoS One 6, e18371.
Bi SH, Jin ZX, Zhang JY, Chen T, Zhang SL, Yang Y, Duan
WX, Yi DH, Zhou JJ, Ren J (2012) Calpain inhibitor MDL
28170 protects against the Ca(2+) paradox in rat hearts.
Clin Exp Pharmacol Physiol 39, 385-392.
Sun MK, Alkon DL (2002) Carbonic anhydrase gating
of attention: Memory therapy and enhancement. Trends
Pharmacol Sci 23, 83-89.
Graham RK, Ehrnhoefer DE, Hayden MR (2011) Caspase6 and neurodegeneration. Trends Neurosci 34, 646-656.
[1134]
[1135]
[1136]
[1137]
[1138]
[1139]
[1140]
[1141]
[1142]
[1143]
[1144]
[1145]
[1146]
[1147]
[1148]
[1149]
[1150]
Rohn TT (2010) The role of caspases in Alzheimer’s disease; potential novel therapeutic opportunities. Apoptosis
15, 1403-1409.
Rohn TT, Head E (2009) Caspases as therapeutic targets
in Alzheimer’s disease: Is it time to “cut” to the chase? Int
J Clin Exp Pathol 2, 108-118.
Rohn TT (2008) Caspase-cleaved TAR DNA-binding
protein-43 is a major pathological finding in Alzheimer’s
disease. Brain Res 1228, 189-198.
Rohn TT, Head E (2008) Caspase activation in Alzheimer’s
disease: Early to rise and late to bed. Rev Neurosci 19,
383-393.
Castro RE, Santos MM, Gloria PM, Ribeiro CJ, Ferreira
DM, Xavier JM, Moreira R, Rodrigues CM (2010) Cell
death targets and potential modulators in Alzheimer’s disease. Curr Pharm Des 16, 2851-2864.
Savitz J, Solms M, Ramesar R (2006) The molecular genetics of cognition: Dopamine, COMT and BDNF. Genes
Brain Behav 5, 311-328.
Tunbridge EM, Harrison PJ, Weinberger DR (2006)
Catechol-o-methyltransferase, cognition, and psychosis:
Val158Met and beyond. Biol Psychiatry 60, 141-151.
Dickinson D, Elvevag B (2009) Genes, cognition and brain
through a COMT lens. Neuroscience 164, 72-87.
Apud JA, Weinberger DR (2007) Treatment of cognitive
deficits associated with schizophrenia: Potential role of
catechol-O-methyltransferase inhibitors. CNS Drugs 21,
535-557.
Gray JA, Roth BL (2007) Molecular targets for treating
cognitive dysfunction in schizophrenia. Schizophr Bull 33,
1100-1119.
Apud JA, Mattay V, Chen J, Kolachana BS, Callicott
JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF,
Goldberg TE, Weinberger DR (2007) Tolcapone improves
cognition and cortical information processing in normal
human subjects. Neuropsychopharmacology 32, 10111020.
Di Giovanni S, Eleuteri S, Paleologou KE, Yin G, Zweckstetter M, Carrupt PA, Lashuel HA (2010) Entacapone and
tolcapone, two catechol O-methyltransferase inhibitors,
block fibril formation of alpha-synuclein and beta-amyloid
and protect against amyloid-induced toxicity. J Biol Chem
285, 14941-14954.
Hook V, Hook G, Kindy M (2010) Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit
and reduce beta-amyloid related to Alzheimer’s disease.
Biol Chem 391, 861-872.
Hook V, Funkelstein L, Wegrzyn J, Bark S, Kindy M,
Hook G (2012) Cysteine Cathepsins in the secretory vesicle produce active peptides: Cathepsin L generates peptide
neurotransmitters and cathepsin B produces beta-amyloid
of Alzheimer’s disease. Biochim Biophys Acta 1824, 89104.
Sundelof J, Sundstrom J, Hansson O, EriksdotterJonhagen M, Giedraitis V, Larsson A, DegermanGunnarsson M, Ingelsson M, Minthon L, Blennow K,
Kilander L, Basun H, Lannfelt L (2010) Higher cathepsin B levels in plasma in Alzheimer’s disease compared to
healthy controls. J Alzheimers Dis 22, 1223-1230.
Hook V, Kindy M, Hook G (2007) Cysteine protease
inhibitors effectively reduce in vivo levels of brain betaamyloid related to Alzheimer’s disease. Biol Chem 388,
247-252.
Hook VY, Kindy M, Hook G (2008) Inhibitors of cathepsin
B improve memory and reduce beta-amyloid in transgenic
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1151]
[1152]
[1153]
[1154]
[1155]
[1156]
[1157]
[1158]
[1159]
[1160]
[1161]
[1162]
Alzheimer disease mice expressing the wild-type, but not
the Swedish mutant, beta-secretase site of the amyloid
precursor protein. J Biol Chem 283, 7745-7753.
Hook VY, Kindy M, Reinheckel T, Peters C, Hook
G (2009) Genetic cathepsin B deficiency reduces betaamyloid in transgenic mice expressing human wild-type
amyloid precursor protein. Biochem Biophys Res Commun
386, 284-288.
Hook G, Hook V, Kindy M (2011) The cysteine protease
inhibitor, E64d, reduces brain amyloid-beta and improves
memory deficits in Alzheimer’s disease animal models
by inhibiting cathepsin B, but not BACE1, beta-secretase
activity. J Alzheimers Dis 26, 387-408.
Hook G, Hook VY, Kindy M (2007) Cysteine protease
inhibitors reduce brain beta-amyloid and beta-secretase
activity in vivo and are potential Alzheimer’s disease therapeutics. Biol Chem 388, 979-983.
Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, Russell DW, Bjorkhem I (2001) On the
turnover of brain cholesterol in patients with Alzheimer’s
disease. Abnormal induction of the cholesterol-catabolic
enzyme CYP46 in glial cells. Neurosci Lett 314, 45-48.
Desai P, DeKosky ST, Kamboh MI (2002) Genetic variation in the cholesterol 24-hydroxylase (CYP46) gene
and the risk of Alzheimer’s disease. Neurosci Lett 328,
9-12.
Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S,
Thal D, Nicosia F, Iakovidou V, Maddalena A, Lutjohann D, Ghebremedhin E, Hegi T, Pasch T, Traxler M,
Bruhl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock
C (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an
intronic CYP46 polymorphism. Arch Neurol 60, 29-35.
Papassotiropoulos A, Lambert JC, Wavrant-De VF,
Wollmer MA, von der KH, Streffer JR, Maddalena A,
Huynh KD, Wolleb S, Lutjohann D, Schneider B, Thal DR,
Grimaldi LM, Tsolaki M, Kapaki E, Ravid R, Konietzko
U, Hegi T, Pasch T, Jung H, Braak H, Amouyel P, Rogaev
EI, Hardy J, Hock C, Nitsch RM (2005) Cholesterol 25hydroxylase on chromosome 10q is a susceptibility gene
for sporadic Alzheimer’s disease. Neurodegener Dis 2,
233-241.
Fernandez DPV, Alvarez AM, Fernandez MM, Galdos
AL, Gomez BF, Pena JA, Afonso-Sanchez MA, Zarranz
Imirizaldu JJ, de Pancorbo MM (2006) Polymorphism in
the cholesterol 24S-hydroxylase gene (CYP46A1) associated with the APOEpsilon3 allele increases the risk of
Alzheimer’s disease and of mild cognitive impairment progressing to Alzheimer’s disease. Dement Geriatr Cogn
Disord 21, 81-87.
Kolsch H, Lutjohann D, Jessen F, Popp J, Hentschel F,
Kelemen P, Schmitz S, Maier W, Heun R (2009) CYP46A1
variants influence Alzheimer’s disease risk and brain
cholesterol metabolism. Eur Psychiatry 24, 183-190.
Fu BY, Ma SL, Tang NL, Tam CW, Lui VW, Chiu HF,
Lam LC (2009) Cholesterol 24-hydroxylase (CYP46A1)
polymorphisms are associated with faster cognitive deterioration in Chinese older persons: A two-year follow up
study. Int J Geriatr Psychiatry 24, 921-926.
Lai CL, Hsu CY, Liou LM, Hsieh HY, Hsieh YH, Liu CK
(2011) Effect of cholesterol and CYP46 polymorphism on
cognitive event-related potentials. Psychophysiology 48,
1572-1577.
Li Y, Chu LW, Wang B, Yik PY, Huriletemuer, Jin DY,
Ma X, Song YQ (2010) CYP46A1 functional promoter
[1163]
[1164]
[1165]
[1166]
[1167]
[1168]
[1169]
[1170]
[1171]
[1172]
[1173]
[1174]
[1175]
[1176]
[1177]
639
haplotypes decipher genetic susceptibility to Alzheimer’s
disease. J Alzheimers Dis 21, 1311-1323.
Lutjohann D (2006) Cholesterol metabolism in the brain:
Importance of 24S-hydroxylation. Acta Neurol Scand
Suppl 185, 33-42.
Garcia AN, Muniz MT, Souza e Silva HR, da Silva
HA, thayde-Junior L (2009) Cyp46 polymorphisms in
Alzheimer’s disease: A review. J Mol Neurosci 39, 342345.
Mast N, White MA, Bjorkhem I, Johnson EF, Stout CD,
Pikuleva IA (2008) Crystal structures of substrate-bound
and substrate-free cytochrome P450 46A1, the principal
cholesterol hydroxylase in the brain. Proc Natl Acad Sci
U S A 105, 9546-9551.
Lund EG, Guileyardo JM, Russell DW (1999) cDNA
cloning of cholesterol 24-hydroxylase, a mediator of
cholesterol homeostasis in the brain. Proc Natl Acad Sci
U S A 96, 7238-7243.
Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell
DW (2003) Knockout of the cholesterol 24-hydroxylase
gene in mice reveals a brain-specific mechanism
of cholesterol turnover. J Biol Chem 278, 2298022988.
Hudry E, Van DD, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P,
Cartier N (2010) Adeno-associated virus gene therapy with
cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse
models of Alzheimer’s disease. Mol Ther 18, 44-53.
Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM,
revalo-Serrano J, Gonzalo-Ruiz A (2012) Oligomers of
beta-amyloid protein (Abeta1-42) induce the activation
of cyclooxygenase-2 in astrocytes via an interaction with
interleukin-1beta, tumour necrosis factor-alpha, and a
nuclear factor kappa-B mechanism in the rat brain. Exp
Neurol 236, 215-227.
McGeer PL, McGeer E, Rogers J, Sibley J (1990) Antiinflammatory drugs and Alzheimer disease. Lancet 335,
1037.
Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease
brain. Neuroscience 87, 319-324.
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik
CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang
DE, Marquez-Sterling N, Golde TE, Koo EH (2001) A
subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212-216.
Weggen S, Rogers M, Eriksen J (2007) NSAIDs: Small
molecules for prevention of Alzheimer’s disease or precursors for future drug development? Trends Pharmacol
Sci 28, 536-543.
Aisen PS (2002) Evaluation of selective COX-2 inhibitors
for the treatment of Alzheimer’s disease. J Pain Symptom
Manage 23, S35-S40.
Golde TE, Erikson JL, Weggen S, Sagi SA, Koo EH (2002)
Nonsteroidal antiinflammatory drugs as therapeutic agents
for Alzheimer’s disease. Drug Dev Res 56, 415-420.
Pasinetti GM (2002) From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer’s
disease: The role of NSAIDs and cyclooxygenase in betaamyloidosis and clinical dementia. J Alzheimers Dis 4,
435-445.
McGeer PL, McGeer EG (2007) NSAIDs and Alzheimer
disease: Epidemiological, animal model and clinical studies. Neurobiol Aging 28, 639-647.
640
[1178]
[1179]
[1180]
[1181]
[1182]
[1183]
[1184]
[1185]
[1186]
[1187]
[1188]
[1189]
[1190]
[1191]
[1192]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Szekely CA, Zandi PP (2010) Non-steroidal antiinflammatory drugs and Alzheimer’s disease: The
epidemiological evidence. CNS Neurol Disord Drug Targets 9, 132-139.
in ‘t Veld, Ruitenberg A, Hofman A, Launer LJ, van
Duijn CM, Stijnen T, Breteler MM, Stricker BH (2001)
Nonsteroidal antiinflammatory drugs and the risk of
Alzheimer’s disease. N Engl J Med 345, 1515-1521.
Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert
C, Piantadosi S, Sabbagh M (2007) Naproxen and celecoxib do not prevent AD in early results from a randomized
controlled trial. Neurology 68, 1800-1808.
Leoutsakos JM, Muthen BO, Breitner JC, Lyketsos CG
(2012) Effects of non-steroidal anti-inflammatory drug
treatments on cognitive decline vary by phase of preclinical Alzheimer disease: Findings from the randomized
controlled Alzheimer’s Disease Anti-inflammatory Prevention Trial. Int J Geriatr Psychiatry 27, 364-374.
Lleo A, Berezovska O, Herl L, Raju S, Deng A, Bacskai
BJ, Frosch MP, Irizarry M, Hyman BT (2004) Nonsteroidal
anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation. Nat Med 10, 1065-1066.
Gasparini L, Ongini E, Wenk G (2004) Non-steroidal antiinflammatory drugs (NSAIDs) in Alzheimer’s disease: Old
and new mechanisms of action. J Neurochem 91, 521-536.
Hirohata M, Ono K, Naiki H, Yamada M (2005)
Non-steroidal anti-inflammatory drugs have antiamyloidogenic effects for Alzheimer’s beta-amyloid
fibrils in vitro. Neuropharmacology 49, 1088-1099.
Hirohata M, Ono K, Yamada M (2008) Non-steroidal antiinflammatory drugs as anti-amyloidogenic compounds.
Curr Pharm Des 14, 3280-3294.
Leuchtenberger S, Beher D, Weggen S (2006) Selective
modulation of Abeta42 production in Alzheimer’s disease:
Non-steroidal anti-inflammatory drugs and beyond. Curr
Pharm Des 12, 4337-4355.
Smith SM, Uslaner JM, Hutson PH (2010) The therapeutic
potential of D-Amino Acid Oxidase (DAAO) inhibitors.
Open Med Chem J 4, 3-9.
Jansen A, Krach S, Krug A, Markov V, Eggermann T,
Zerres K, Thimm M, Nothen MM, Treutlein J, Rietschel
M, Kircher T (2009) Effect of the G72 (DAOA) putative
risk haplotype on cognitive functions in healthy subjects.
BMC Psychiatry 9, 60.
Jansen A, Krach S, Krug A, Markov V, Eggermann T,
Zerres K, Stocker T, Shah NJ, Nothen MM, Treutlein J,
Rietschel M, Kircher T (2009) A putative high risk diplotype of the G72 gene is in healthy individuals associated
with better performance in working memory functions and
altered brain activity in the medial temporal lobe. Neuroimage 45, 1002-1008.
Jansen A, Krach S, Krug A, Markov V, Thimm M, Paulus
FM, Zerres K, Stocker T, Shah NJ, Nothen MM, Treutlein J, Rietschel M, Kircher T (2010) The effect of G72
genotype on neural correlates of memory encoding and
retrieval. Neuroimage 53, 1001-1006.
Otte DM, Sommersberg B, Kudin A, Guerrero C,
Albayram O, Filiou MD, Frisch P, Yilmaz O, Drews E,
Turck CW, Bilkei-Gorzo A, Kunz WS, Beck H, Zimmer
A (2011) N-acetyl cysteine treatment rescues cognitive
deficits induced by mitochondrial dysfunction in G72/G30
transgenic mice. Neuropsychopharmacology 36, 22332243.
Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause
G, Willbold D, Funke SA, Schilling S, Demuth HU
[1193]
[1194]
[1195]
[1196]
[1197]
[1198]
[1199]
[1200]
[1201]
[1202]
[1203]
[1204]
(2009) Pyroglutamate formation influences solubility and
amyloidogenicity of amyloid peptides. Biochemistry 48,
7072-7078.
Schlenzig D, Ronicke R, Cynis H, Ludwig HH, Scheel E,
Reymann K, Saido T, Hause G, Schilling S, Demuth HU
(2012) N-Terminal pyroglutamate formation of Abeta38
and Abeta40 enforces oligomer formation and potency to
disrupt hippocampal long-term potentiation. J Neurochem
121, 774-784.
Morawski M, Hartlage-Rubsamen M, Jager C, Waniek A,
Schilling S, Schwab C, McGeer PL, Arendt T, Demuth HU,
Rossner S (2010) Distinct glutaminyl cyclase expression
in Edinger-Westphal nucleus, locus coeruleus and nucleus
basalis Meynert contributes to pGlu-Abeta pathology in
Alzheimer’s disease. Acta Neuropathol 120, 195-207.
Hartlage-Rubsamen M, Morawski M, Waniek A, Jager C,
Zeitschel U, Koch B, Cynis H, Schilling S, Schliebs R,
Demuth HU, Rossner S (2011) Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate
(pGlu)-Abeta deposits in hippocampus via distinct cellular
mechanisms. Acta Neuropathol 121, 705-719.
Jawhar S, Wirths O, Schilling S, Graubner S, Demuth HU,
Bayer TA (2011) Overexpression of glutaminyl cyclase,
the enzyme responsible for pyroglutamate Abeta formation, induces behavioral deficits, and glutaminyl cyclase
knock-out rescues the behavioral phenotype in 5XFAD
mice. J Biol Chem 286, 4454-4460.
Jawhar S, Wirths O, Bayer TA (2011) Pyroglutamate
amyloid-beta (Abeta): A hatchet man in Alzheimer disease. J Biol Chem 286, 38825-38832.
Schilling S, Niestroj AJ, Rahfeld JU, Hoffmann T, Wermann M, Zunkel K, Wasternack C, Demuth HU (2003)
Identification of human glutaminyl cyclase as a metalloenzyme. Potent inhibition by imidazole derivatives and
heterocyclic chelators. J Biol Chem 278, 49773-49779.
Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E,
Bohm G, Demuth HU (2006) On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry
45, 12393-12399.
Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke
M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M,
Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph
T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S
(2008) Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat
Med 14, 1106-1111.
Schilling S, Appl T, Hoffmann T, Cynis H, Schulz
K, Jagla W, Friedrich D, Wermann M, Buchholz M,
Heiser U, von HS, Demuth HU (2008) Inhibition of
glutaminyl cyclase prevents pGlu-Abeta formation after
intracortical/hippocampal microinjection in vivo/in situ. J
Neurochem 106, 1225-1236.
Cynis H, Schilling S, Bodnar M, Hoffmann T, Heiser U,
Saido TC, Demuth HU (2006) Inhibition of glutaminyl
cyclase alters pyroglutamate formation in mammalian
cells. Biochim Biophys Acta 1764, 1618-1625.
Cynis H, Scheel E, Saido TC, Schilling S, Demuth HU
(2008) Amyloidogenic processing of amyloid precursor
protein: Evidence of a pivotal role of glutaminyl cyclase in
generation of pyroglutamate-modified amyloid-beta. Biochemistry 47, 7405-7413.
Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson
E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Ronicke
R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W,
Graubner S, Glabe CG, Demuth HU, Bloom GS (2012)
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1204]
[1205]
[1206]
[1207]
[1208]
[1209]
[1210]
[1211]
[1212]
[1213]
[1214]
[1215]
[1216]
[1217]
[1218]
Prion-like behaviour and tau-dependent cytotoxicity of
pyroglutamylated amyloid-beta. Nature 485, 651-655.
[4]Koch B, Buchholz M, Wermann M, Heiser U, Schilling
S, Demuth HU (2012) Probing Secondary GlutaminylCyclase (QC)-Inhibitor Interactions. Chem Biol Drug Des,
doi: 10.1111/cbdd.12046.Sultana R, Boyd-Kimball D, Cai J, Pierce WM, Klein JB,
Merchant M, Butterfield DA (2007) Proteomics analysis of the Alzheimer’s disease hippocampal proteome. J
Alzheimers Dis 11, 153-164.
Shalova IN, Cechalova K, Rehakova Z, Dimitrova P,
Ognibene E, Caprioli A, Schmalhausen EV, Muronetz
VI, Saso L (2007) Decrease of dehydrogenase activity
of cerebral glyceraldehyde-3-phosphate dehydrogenase in
different animal models of Alzheimer’s disease. Biochim
Biophys Acta 1770, 826-832.
Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler
P, Muller D, van OJ, Waldmeier P, Furst P (1998)
Glyceraldehyde-3-phosphate dehydrogenase, the putative
target of the antiapoptotic compounds CGP 3466 and R-()-deprenyl. J Biol Chem 273, 5821-5828.
Zimmermann K, Roggo S, Kragten E, Furst P, Waldmeier
P (1998) Synthesis of tools for target identification of the
anti-apoptotic compound CGP 3466; Part I. Bioorg Med
Chem Lett 8, 1195-1200.
Andringa G, Cools AR (2000) The neuroprotective effects
of CGP 3466B in the best in vivo model of Parkinson’s
disease, the bilaterally MPTP-treated rhesus monkey. J
Neural Transm Suppl 215-225.
Andringa G, van Oosten RV, Unger W, Hafmans TG,
Veening J, Stoof JC, Cools AR (2000) Systemic administration of the propargylamine CGP 3466B prevents
behavioural and morphological deficits in rats with 6hydroxydopamine-induced lesions in the substantia nigra.
Eur J Neurosci 12, 3033-3043.
Andringa G, Eshuis S, Perentes E, Maguire RP, Roth D,
Ibrahim M, Leenders KL, Cools AR (2003) TCH346 prevents motor symptoms and loss of striatal FDOPA uptake
in bilaterally MPTP-treated primates. Neurobiol Dis 14,
205-217.
Sagot Y, Toni N, Perrelet D, Lurot S, King B, Rixner H,
Mattenberger L, Waldmeier PC, Kato AC (2000) An orally
active anti-apoptotic molecule (CGP 3466B) preserves
mitochondria and enhances survival in an animal model
of motoneuron disease. Br J Pharmacol 131, 721-728.
Waldmeier PC, Spooren WP, Hengerer B (2000) CGP 3466
protects dopaminergic neurons in lesion models of Parkinson’s disease. Naunyn Schmiedebergs Arch Pharmacol
362, 526-537.
Waldmeier PC, Boulton AA, Cools AR, Kato AC, Tatton
WG (2000) Neurorescuing effects of the GAPDH ligand
CGP 3466B. J Neural Transm Suppl 197-214.
Waldmeier PC (2003) Prospects for antiapoptotic drug
therapy of neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 27, 303-321.
Matarredona ER, Meyer M, Seiler RW, Widmer HR (2003)
CGP 3466 increases survival of cultured fetal dopaminergic neurons. Restor Neurol Neurosci 21, 29-37.
Hara MR, Thomas B, Cascio MB, Bae BI, Hester
LD, Dawson VL, Dawson TM, Sawa A, Snyder SH
(2006) Neuroprotection by pharmacologic blockade of the
GAPDH death cascade. Proc Natl Acad Sci U S A 103,
3887-3889.
Olanow CW, Schapira AH, LeWitt PA, Kieburtz K, Sauer
D, Olivieri G, Pohlmann H, Hubble J (2006) TCH346 as
[1219]
[1220]
[1221]
[1222]
[1223]
[1224]
[1225]
[1226]
[1227]
[1228]
[1229]
[1230]
[1231]
[1232]
[1233]
[1234]
[1235]
641
a neuroprotective drug in Parkinson’s disease: A doubleblind, randomised, controlled trial. Lancet Neurol 5, 10131020.
Miller R, Bradley W, Cudkowicz M, Hubble J, Meininger
V, Mitsumoto H, Moore D, Pohlmann H, Sauer D, Silani V,
Strong M, Swash M, Vernotica E (2007) Phase II/III randomized trial of TCH346 in patients with ALS. Neurology
69, 776-784.
Erb M, Meinen S, Barzaghi P, Sumanovski LT, CourdierFruh I, Ruegg MA, Meier T (2009) Omigapil ameliorates
the pathology of muscle dystrophy caused by lamininalpha2 deficiency. J Pharmacol Exp Ther 331, 787-795.
Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Ruegg MA
(2011) Apoptosis inhibitors and mini-agrin have additive
benefits in congenital muscular dystrophy mice. EMBO
Mol Med 3, 465-479.
Munoz-Montano JR, Lim F, Moreno FJ, Avila J, Diaz-Nido
J (1999) Glycogen synthase kinase-3 modulates neurite
outgrowth in cultured neurons: Possible implications for
neurite pathology in Alzheimer’s disease. J Alzheimers Dis
1, 361-378.
Eldar-Finkelman H (2002) Glycogen synthase kinase 3:
An emerging therapeutic target. Trends Mol Med 8, 126132.
Martinez A, Alonso M, Castro A, Perez C, Moreno
FJ (2002) First non-ATP competitive glycogen synthase
kinase 3 beta (GSK-3beta) inhibitors: Thiadiazolidinones
(TDZD) as potential drugs for the treatment of Alzheimer’s
disease. J Med Chem 45, 1292-1299.
Martinez A, Castro A, Dorronsoro I, Alonso M (2002)
Glycogen synthase kinase 3 (GSK-3) inhibitors as new
promising drugs for diabetes, neurodegeneration, cancer,
and inflammation. Med Res Rev 22, 373-384.
Bhat RV, Budd Haeberlein SL, Avila J (2004) Glycogen
synthase kinase 3: A drug target for CNS therapies. J
Neurochem 89, 1313-1317.
Cohen P, Goedert M (2004) GSK3 inhibitors: Development and therapeutic potential. Nat Rev Drug Discov 3,
479-487.
Meijer L, Flajolet M, Greengard P (2004) Pharmacological
inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 25, 471-480.
Chin PC, Majdzadeh N, D’Mello SR (2005) Inhibition
of GSK3beta is a common event in neuroprotection by
different survival factors. Brain Res Mol Brain Res 137,
193-201.
Huang HC, Klein PS (2006) Multiple roles for glycogen
synthase kinase-3 as a drug target in Alzheimer’s disease.
Curr Drug Targets 7, 1389-1397.
Muyllaert D, Terwel D, Borghgraef P, Devijver H,
Dewachter I, Van Leuven F (2006) Transgenic mouse
models for Alzheimer’s disease: The role of GSK-3B in
combined amyloid and tau-pathology. Rev Neurol (Paris)
162, 903-907.
Takashima A (2006) GSK-3 is essential in the pathogenesis
of Alzheimer’s disease. J Alzheimers Dis 9(3 Suppl), 309317.
Avila J, Hernandez F (2007) GSK-3 inhibitors for
Alzheimer’s disease. Expert Rev Neurother 7, 1527-1533.
Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative
diseases. Nat Rev Drug Discov 6, 464-479.
Hooper C, Killick R, Lovestone S (2008) The GSK3
hypothesis of Alzheimer’s disease. J Neurochem 104,
1433-1439.
642
[1236]
[1237]
[1238]
[1239]
[1240]
[1241]
[1242]
[1243]
[1244]
[1245]
[1246]
[1247]
[1248]
[1249]
[1250]
[1251]
[1252]
[1253]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Martinez A (2008) Preclinical efficacy on GSK-3
inhibitors: Towards a future generation of powerful drugs.
Med Res Rev 28, 773-796.
Martinez A, Perez DI (2008) GSK-3 inhibitors: A ray
of hope for the treatment of Alzheimer’s disease? J
Alzheimers Dis 15, 181-191.
Medina M, Castro A (2008) Glycogen synthase kinase3 (GSK-3) inhibitors reach the clinic. Curr Opin Drug
Discov Devel 11, 533-543.
Muyllaert D, Kremer A, Jaworski T, Borghgraef P, Devijver H, Croes S, Dewachter I, Van Leuven F (2008)
Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology? Genes Brain Behav 7(Suppl 1),
57-66.
Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes
S, Devijver H, Van Leuven F (2008) Amyloid activates
GSK-3beta to aggravate neuronal tauopathy in bigenic
mice. Am J Pathol 172, 786-798.
Dewachter I, Ris L, Jaworski T, Seymour CM, Kremer
A, Borghgraef P, De VH, Godaux E, Van Leuven F
(2009) GSK3beta, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory
phosphorylation at serine-9. Neurobiol Dis 35, 193200.
Giese KP (2009) GSK-3: A key player in neurodegeneration and memory. IUBMB Life 61, 516-521.
Zhou XW, Winblad B, Guan Z, Pei JJ (2009) Interactions
between glycogen synthase kinase 3beta, protein kinase
B, and protein phosphatase 2A in tau phosphorylation in
mouse N2a neuroblastoma cells. J Alzheimers Dis 17, 929937.
Avila. J, Wandosell F, Hernandez F (2010) Role of glycogen synthase kinase-3 in Alzheimer’s disease pathogenesis
and glycogen synthase kinase-3 inhibitors. Expert Rev
Neurother 10, 703-710.
Lei P, Ayton S, Bush AI, Adlard PA (2011) GSK-3 in
Neurodegenerative Diseases. Int J Alzheimers Dis 2011,
189246.
Martinez A, Gil C, Perez DI (2011) Glycogen synthase
kinase 3 inhibitors in the next horizon for Alzheimer’s
disease treatment. Int J Alzheimers Dis 2011, 280502.
Eldar-Finkelman H, Martinez A (2011) GSK-3 inhibitors:
preclinical and clinical focus on CNS. Front Mol Neurosci
4, 32.
Mines MA, Jope RS (2011) Glycogen synthase kinase3: A promising therapeutic target for fragile x syndrome.
Front Mol Neurosci 4, 35.
Mines MA, Beurel E, Jope RS (2011) Regulation of cell
survival mechanisms in Alzheimer’s disease by glycogen
synthase kinase-3. Int J Alzheimers Dis 2011, 861072.
Kremer A, Louis JV, Jaworski T, Van Leuven F (2011)
GSK3 and Alzheimer’s disease: Facts and fiction. Front
Mol Neurosci 4, 17.
Amar S, Belmaker RH, Agam G (2011) The possible
involvement of glycogen synthase kinase-3 (GSK-3) in
diabetes, cancer and central nervous system diseases. Curr
Pharm Des 17, 2264-2277.
Martin L, Page G, Terro F (2011) Tau phosphorylation
and neuronal apoptosis induced by the blockade of PP2A
preferentially involve GSK3beta. Neurochem Int 59, 235250.
Avila J, Leon-Espinosa G, Garcia E, Garcia-Escudero V,
Hernandez F, Defelipe J (2012) Tau phosphorylation by
GSK3 in different conditions. Int J Alzheimers Dis 2012,
578373.
[1254]
[1255]
[1256]
[1257]
[1258]
[1259]
[1260]
[1261]
[1262]
[1263]
[1264]
[1265]
[1266]
[1267]
Hernandez F, Lucas JJ, Avila J (2012) GSK3 and tau: Two
convergence points in Alzheimer’s disease. J Alzheimers
Dis, doi: 10.3233/JAD-2012-129025 [Epubl ahead of
print].
Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ (2012)
AGEs induce Alzheimer-like tau pathology and memory
deficit via RAGE-mediated GSK-3 activation. Neurobiol
Aging 33, 1400-1410.
Mondragon-Rodriguez S, Perry G, Zhu X, Moreira PI,
Williams S (2012) Glycogen synthase kinase 3: A point of
integration in Alzheimer’s disease and a therapeutic target?
Int J Alzheimers Dis 2012, 276803.
Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG,
Cotte A, Jaworski T, Tobon-Velasco JC, Devijver H,
Garcia-Mayoral MF, Van Leuven F, Hayes JD, Bertho G,
Cuadrado A (2012) Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase
3/beta-TrCP axis. Mol Cell Biol 32, 3486-3499.
Rocha-Souto B, Coma M, Perez-Nievas BG, Scotton TC,
Siao M, Sanchez-Ferrer P, Hashimoto T, Fan Z, Hudry
E, Barroeta I, Sereno L, Rodriguez M, Sanchez MB,
Hyman BT, Gomez-Isla T (2012) Activation of glycogen synthase kinase-3 beta mediates beta-amyloid induced
neuritic damage in Alzheimer’s disease. Neurobiol Dis 45,
425-437.
Cai Z, Zhao Y, Zhao B (2012) Roles of glycogen synthase
kinase 3 in Alzheimer’s disease. Curr Alzheimer Res, in
press. [Epubl ahead of print].
Parr C, Carzaniga R, Gentleman S, Van Leuven F,
Walter J, Sastre M (2012) GSK3 inhibition promotes
lysosomal biogenesis and the autophagic degradation of
the amyloid-beta precursor protein. Mol Cell Biol, doi:
10.1128/MCB.00930-12 [Epubl ahead of print].
Dajani R, Fraser E, Roe SM, Young N, Good V, Dale
TC, Pearl LH (2001) Crystal structure of glycogen synthase kinase 3 beta: Structural basis for phosphate-primed
substrate specificity and autoinhibition. Cell 105, 721732.
Ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson
L, Jain J (2001) Structure of GSK3beta reveals a primed
phosphorylation mechanism. Nat Struct Biol 8, 593-596.
Martinez A, Alonso M, Castro A, Dorronsoro I, Gelpi JL,
Luque FJ, Perez C, Moreno FJ (2005) SAR and 3D-QSAR
studies on thiadiazolidinone derivatives: Exploration of
structural requirements for glycogen synthase kinase 3
inhibitors. J Med Chem 48, 7103-7112.
Akhtar M, Bharatam PV (2012) 3D-QSAR and molecular
docking studies on 3-anilino-4-arylmaleimide derivatives
as glycogen synthase kinase-3beta inhibitors. Chem Biol
Drug Des 79, 560-571.
Karpov PV, Osolodkin DI, Baskin II, Palyulin VA, Zefirov
NS (2011) One-class classification as a novel method of
ligand-based virtual screening: The case of glycogen synthase kinase 3beta inhibitors. Bioorg Med Chem Lett 21,
6728-6731.
Osolodkin DI, Palyulin VA, Zefirov NS (2011) Structurebased virtual screening of glycogen synthase kinase 3beta
inhibitors: Analysis of scoring functions applied to large
true actives and decoy sets. Chem Biol Drug Des 78, 378390.
Castro A, Encinas A, Gil C, Brase S, Porcal W, Perez
C, Moreno FJ, Martinez A (2008) Non-ATP competitive
glycogen synthase kinase 3beta (GSK-3beta) inhibitors:
Study of structural requirements for thiadiazolidinone
derivatives. Bioorg Med Chem 16, 495-510.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1268]
[1269]
[1270]
[1271]
[1272]
[1273]
[1274]
[1275]
[1276]
[1277]
[1278]
[1279]
del Ser T, Steinwachs KC, Gertz HJ, Andres MV, GomezCarrillo B, Medina M, Vericat JA, Redondo P, Fleet D,
Leon T (2012) Treatment of Alzheimer’s disease with the
GSK-3 inhibitor tideglusib: A pilot study. J Alzheimers
Dis, doi: 10.3233/JAD-2012-120805 [Epubl ahead of
print].
Cociorva OM, Li B, Nomanbhoy T, Li Q, Nakamura A,
Nakamura K, Nomura M, Okada K, Seto S, Yumoto K,
Liyanage M, Zhang MC, Aban A, Leen B, Szardenings
AK, Rosenblum JS, Kozarich JW, Kohno Y, Shreder KR
(2011) Synthesis and structure-activity relationship of 4quinolone-3-carboxylic acid based inhibitors of glycogen
synthase kinase-3beta. Bioorg Med Chem Lett 21, 59485951.
Coffman K, Brodney M, Cook J, Lanyon L, Pandit
J, Sakya S, Schachter J, Tseng-Lovering E, Wessel
M (2011) 6-amino-4-(pyrimidin-4-yl)pyridones: Novel
glycogen synthase kinase-3beta inhibitors. Bioorg Med
Chem Lett 21, 1429-1433.
Saitoh M, Kunitomo J, Kimura E, Hayase Y, Kobayashi H,
Uchiyama N, Kawamoto T, Tanaka T, Mol CD, Dougan
DR, Textor GS, Snell GP, Itoh F (2009) Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole
derivatives as novel inhibitors of glycogen synthase kinase3beta. Bioorg Med Chem 17, 2017-2029.
Saitoh M, Kunitomo J, Kimura E, Iwashita H, Uno Y,
Onishi T, Uchiyama N, Kawamoto T, Tanaka T, Mol
CD, Dougan DR, Textor GP, Snell GP, Takizawa M,
Itoh F, Kori M (2009) 2-3-[4-(Alkylsulfinyl)phenyl]-1benzofuran-5-yl-5-methyl-1,3,4-oxadiazol e derivatives as
novel inhibitors of glycogen synthase kinase-3beta with
good brain permeability. J Med Chem 52, 6270-6286.
Saitoh M, Kunitomo J, Kimura E, Yamano T, Itoh F, Kori
M (2010) Enantioselective synthesis of the novel chiral
sulfoxide derivative as a glycogen synthase kinase 3beta
inhibitor. Chem Pharm Bull (Tokyo) 58, 1252-1254.
Onishi T, Iwashita H, Uno Y, Kunitomo J, Saitoh M,
Kimura E, Fujita H, Uchiyama N, Kori M, Takizawa M
(2011) A novel glycogen synthase kinase-3 inhibitor 2methyl-5-(3-4-[(S )-methylsulfinyl]phenyl-1-benzofuran5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and
ameliorates cognitive deficits in a transgenic model of
Alzheimer’s disease. J Neurochem 119, 1330-1340.
Ding S, Wu TY, Brinker A, Peters EC, Hur W, Gray NS,
Schultz PG (2003) Synthetic small molecules that control stem cell fate. Proc Natl Acad Sci U S A 100, 76327637.
Paterniti I, Mazzon E, Gil C, Impellizzeri D, Palomo V,
Redondo M, Perez DI, Esposito E, Martinez A, Cuzzocrea
S (2011) PDE 7 inhibitors: New potential drugs for the
therapy of spinal cord injury. PLoS One 6, e15937.
Lipina TV, Palomo V, Gil C, Martinez A, Roder JC (2013)
Dual inhibitor of PDE7 and GSK-3 - VP1.15 acts as
antipsychotic and cognitive enhancer in C57BL/6J mice.
Neuropharmacology 61, 205-214.
Bhat R, Xue Y, Berg S, Hellberg S, Ormo M, Nilsson
Y, Radesater AC, Jerning E, Markgren PO, Borgegard T,
Nylof M, Gimenez-Cassina A, Hernandez F, Lucas JJ, azNido J, Avila J (2003) Structural insights and biological
effects of glycogen synthase kinase 3-specific inhibitor
AR-A014418. J Biol Chem 278, 45937-45945.
Gould TD, Einat H, Bhat R, Manji HK (2004)
AR-A014418, a selective GSK-3 inhibitor, produces
antidepressant-like effects in the forced swim test. Int J
Neuropsychopharmacol 7, 387-390.
[1280]
[1281]
[1282]
[1283]
[1284]
[1285]
[1286]
[1287]
[1288]
[1289]
[1290]
643
Berg S, Bergh M, Hellberg S, Hogdin K, Lo-Alfredsson Y,
Soderman P, von BS, Weigelt T, Ormo M, Xue Y, Tucker J,
Neelissen J, Jerning E, Nilsson Y, Bhat R (2012) Discovery of novel potent and highly selective glycogen synthase
kinase-3beta (GSK3beta) inhibitors for Alzheimer’s disease: Design, synthesis, and characterization of pyrazines.
J Med Chem, doi: 10.1021/jm201742m [Epubl ahead of
print].
Koryakova AG, Ivanenkov YA, Ryzhova EA, Bulanova
EA, Karapetian RN, Mikitas OV, Katrukha EA,
Kazey VI, Okun I, Kravchenko DV, Lavrovsky YV,
Korzinov OM, Ivachtchenko AV (2008) Novel aryl
and heteroaryl substituted N-[3-(4-phenylpiperazin-1yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective
GSK-3 inhibitors. Bioorg Med Chem Lett 18, 36613666.
Macaulay K, Hajduch E, Blair AS, Coghlan MP, Smith
SA, Hundal HS (2003) Use of lithium and SB-415286
to explore the role of glycogen synthase kinase-3 in the
regulation of glucose transport and glycogen synthase. Eur
J Biochem 270, 3829-3838.
Pizarro JG, Yeste-Velasco M, Rimbau V, Casadesus
G, Smith MA, Pallas M, Folch J, Camins A (2008)
Neuroprotective effects of SB-415286 on hydrogen
peroxide-induced cell death in B65 rat neuroblastoma cells
and neurons. Int J Dev Neurosci 26, 269-276.
Pizarro JG, Folch J, Esparza JL, Jordan J, Pallas M, Camins
A (2009) A molecular study of pathways involved in the
inhibition of cell proliferation in neuroblastoma B65 cells
by the GSK-3 inhibitors lithium and SB-415286. J Cell
Mol Med 13, 3906-3917.
Yeste-Velasco M, Folch J, Jimenez A, Rimbau V, Pallas M,
Camins A (2008) GSK-3 beta inhibition and prevention
of mitochondrial apoptosis inducing factor release are not
involved in the antioxidant properties of SB-415286. Eur
J Pharmacol 588, 239-243.
Gentile G, Bernasconi G, Pozzan A, Merlo G, Marzorati
P, Bamborough P, Bax B, Bridges A, Brough C, Carter
P, Cutler G, Neu M, Takada M (2011) Identification of
2-(4-pyridyl)thienopyridinones as GSK-3beta inhibitors.
Bioorg Med Chem Lett 21, 4823-4827.
Gentile G, Merlo G, Pozzan A, Bernasconi G, Bax B, Bamborough P, Bridges A, Carter P, Neu M, Yao G, Brough
C, Cutler G, Coffin A, Belyanskaya S (2012) 5-Aryl-4carboxamide-1,3-oxazoles: Potent and selective GSK-3
inhibitors. Bioorg Med Chem Lett 22, 1989-1994.
Vadivelan S, Sinha BN, Tajne S, Jagarlapudi SA (2009)
Fragment and knowledge-based design of selective GSK3beta inhibitors using virtual screening models. Eur J Med
Chem 44, 2361-2371.
Kuo GH, Prouty C, Deangelis A, Shen L, O’Neill DJ,
Shah C, Connolly PJ, Murray WV, Conway BR, Cheung
P, Westover L, Xu JZ, Look RA, Demarest KT, Emanuel
S, Middleton SA, Jolliffe L, Beavers MP, Chen X (2003)
Synthesis and discovery of macrocyclic polyoxygenated
bis-7-azaindolylmaleimides as a novel series of potent and
highly selective glycogen synthase kinase-3beta inhibitors.
J Med Chem 46, 4021-4031.
O’Neill DJ, Shen L, Prouty C, Conway BR, Westover L,
Xu JZ, Zhang HC, Maryanoff BE, Murray WV, Demarest
KT, Kuo GH (2004) Design, synthesis, and biological
evaluation of novel 7-azaindolyl-heteroaryl-maleimides
as potent and selective glycogen synthase kinase-3beta
(GSK-3beta) inhibitors. Bioorg Med Chem 12, 31673185.
644
[1291]
[1292]
[1293]
[1294]
[1295]
[1296]
[1297]
[1298]
[1299]
[1300]
[1301]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Shen L, Prouty C, Conway BR, Westover L, Xu JZ,
Look RA, Chen X, Beavers MP, Roberts J, Murray WV, Demarest KT, Kuo GH (2004) Synthesis
and biological evaluation of novel macrocyclic bis7-azaindolylmaleimides as potent and highly selective
glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors.
Bioorg Med Chem 12, 1239-1255.
Zhang HC, Ye H, Conway BR, Derian CK, Addo MF,
Kuo GH, Hecker LR, Croll DR, Li J, Westover L, Xu JZ,
Look R, Demarest KT, ndrade-Gordon P, Damiano BP,
Maryanoff BE (2004) 3-(7-Azaindolyl)-4-arylmaleimides
as potent, selective inhibitors of glycogen synthase kinase3. Bioorg Med Chem Lett 14, 3245-3250.
Lum C, Kahl J, Kessler L, Kucharski J, Lundstrom J, Miller
S, Nakanishi H, Pei Y, Pryor K, Roberts E, Sebo L, Sullivan R, Urban J, Wang Z (2008) 2,5-Diaminopyrimidines
and 3,5-disubstituted azapurines as inhibitors of glycogen
synthase kinase-3 (GSK-3). Bioorg Med Chem Lett 18,
3578-3581.
Engler TA, Henry JR, Malhotra S, Cunningham B,
Furness K, Brozinick J, Burkholder TP, Clay MP, Clayton J, Diefenbacher C, Hawkins E, Iversen PW, Li
Y, Lindstrom TD, Marquart AL, McLean J, Mendel
D, Misener E, Briere D, O’toole JC, Porter WJ,
Queener S, Reel JK, Owens RA, Brier RA, Eessalu TE,
Wagner JR, Campbell RM, Vaughn R (2004) Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-dion es as
highly selective and potent inhibitors of glycogen synthase
kinase-3. J Med Chem 47, 3934-3937.
Engler TA, Malhotra S, Burkholder TP, Henry JR, Mendel
D, Porter WJ, Furness K, Diefenbacher C, Marquart A,
Reel JK, Li Y, Clayton J, Cunningham B, McLean J,
O’toole JC, Brozinick J, Hawkins E, Misener E, Briere
D, Brier RA, Wagner JR, Campbell RM, Anderson BD,
Vaughn R, Bennett DB, Meier TI, Cook JA (2005) The
development of potent and selective bisarylmaleimide
GSK3 inhibitors. Bioorg Med Chem Lett 15, 899-903.
Magnus NA, Ley CP, Pollock PM, Wepsiec JP (2010)
Pictet-Spengler based synthesis of a bisarylmaleimide
glycogen synthase kinase-3 inhibitor. Org Lett 12, 37003703.
Gong L, Hirschfeld D, Tan YC, Heather HJ, Peltz G, Avnur
Z, Dunten P (2010) Discovery of potent and bioavailable
GSK-3beta inhibitors. Bioorg Med Chem Lett 20, 16931696.
Arnost M, Pierce A, Ter HE, Lauffer D, Madden J, Tanner
K, Green J (2010) 3-Aryl-4-(arylhydrazono)-1H-pyrazol5-ones: Highly ligand efficient and potent inhibitors of
GSK3beta. Bioorg Med Chem Lett 20, 1661-1664.
Shin D, Lee SC, Heo YS, Lee WY, Cho YS, Kim YE, Hyun
YL, Cho JM, Lee YS, Ro S (2007) Design and synthesis of 7-hydroxy-1H-benzoimidazole derivatives as novel
inhibitors of glycogen synthase kinase-3beta. Bioorg Med
Chem Lett 17, 5686-5689.
Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe
SM, Pearl L, Leost M, Greengard P, Meijer L (2004)
Structural basis for the synthesis of indirubins as potent
and selective inhibitors of glycogen synthase kinase-3 and
cyclin-dependent kinases. J Med Chem 47, 935-946.
Sereno L, Coma M, Rodriguez M, Sanchez-Ferrer P,
Sanchez MB, Gich I, Agullo JM, Perez M, Avila J,
Guardia-Laguarta C, Clarimon J, Lleo A, Gomez-Isla T
(2009) A novel GSK-3beta inhibitor reduces Alzheimer’s
[1302]
[1303]
[1304]
[1305]
[1306]
[1307]
[1308]
[1309]
[1310]
[1311]
[1312]
pathology and rescues neuronal loss in vivo. Neurobiol Dis
35, 359-367.
Stukenbrock H, Mussmann R, Geese M, Ferandin Y,
Lozach O, Lemcke T, Kegel S, Lomow A, Burk U,
Dohrmann C, Meijer L, Austen M, Kunick C (2008) 9cyano-1-azapaullone (cazpaullone), a glycogen synthase
kinase-3 (GSK-3) inhibitor activating pancreatic beta cell
protection and replication. J Med Chem 51, 2196-2207.
Rochais C, Lescot E, Lisowski V, Lepailleur A, Santos
JS, Bureau R, Dallemagne P, Meijer L, Rault S (2004)
Synthesis and biological evaluation of thienopyrrolizines,
a new family of CDK/GSK-3 inhibitors. J Enzyme Inhib
Med Chem 19, 585-593.
Rochais C, Duc NV, Lescot E, Sopkova-de Oliveira SJ,
Bureau R, Meijer L, Dallemagne P, Rault S (2009) Synthesis of new dipyrrolo- and furopyrrolopyrazinones related
to tripentones and their biological evaluation as potential
kinases (CDKs1-5, GSK-3) inhibitors. Eur J Med Chem
44, 708-716.
Kozikowski AP, Gaisina IN, Petukhov PA, Sridhar J,
King LT, Blond SY, Duka T, Rusnak M, Sidhu A (2006)
Highly potent and specific GSK-3beta inhibitors that block
tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson’s disease.
ChemMedChem 1, 256-266.
Kozikowski AP, Gaisina IN, Yuan H, Petukhov PA,
Blond SY, Fedolak A, Caldarone B, McGonigle P (2007)
Structure-based design leads to the identification of lithium
mimetics that block mania-like effects in rodents. possible
new GSK-3beta therapies for bipolar disorders. J Am Chem
Soc 129, 8328-8332.
Kozikowski AP, Gunosewoyo H, Guo S, Gaisina IN,
Walter RL, Ketcherside A, McClung CA, Mesecar
AD, Caldarone B (2011) Identification of a glycogen
synthase kinase-3beta inhibitor that attenuates hyperactivity in CLOCK mutant mice. ChemMedChem 6, 15931602.
Gaisina IN, Gallier F, Ougolkov AV, Kim KH, Kurome
T, Guo S, Holzle D, Luchini DN, Blond SY, Billadeau
DD, Kozikowski AP (2009) From a natural product lead
to the identification of potent and selective benzofuran3-yl-(indol-3-yl)maleimides as glycogen synthase kinase
3beta inhibitors that suppress proliferation and survival
of pancreatic cancer cells. J Med Chem 52, 18531863.
Chen W, Gaisina IN, Gunosewoyo H, Malekiani SA, Hanania T, Kozikowski AP (2011) Structure-guided design of a
highly selective glycogen synthase kinase-3beta inhibitor:
A superior neuroprotective pyrazolone showing antimania
effects. ChemMedChem 6, 1587-1592.
Chen PC, Gaisina IN, El-Khodor BF, Ramboz S, Makhortova NR, Rubin LL, Kozikowski AP (2012) Identification
of a maleimide-based glycogen synthase kinase-3 (GSK3) inhibitor, BIP-135, that prolongs the median survival
time of Delta7 SMA KO mouse model of spinal muscular
atrophy. ACS Chem Neurosci 3, 5-11.
Lo Monte F, Kramer T, Bolander A, Plotkin B, EldarFinkelman H, Fuertes A, Dominguez J, Schmidt B (2011)
Synthesis and biological evaluation of glycogen synthase
kinase 3 (GSK-3) inhibitors: An fast and atom efficient
access to 1-aryl-3-benzylureas. Bioorg Med Chem Lett 21,
5610-5615.
Lo Monte F, Kramer T, Gu J, Brodrecht M, Pilakowski J,
Fuertes A, Dominguez JM, Plotkin B, Eldar-Finkelman
H, Schmidt B (2012) Structure-based optimization of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1313]
[1314]
[1315]
[1316]
[1317]
[1318]
[1319]
[1320]
[1321]
[1322]
[1323]
[1324]
[1325]
[1326]
oxadiazole-based GSK-3 inhibitors. Eur J Med Chem, doi:
10.1016/j.ejmech.2012.06.006 [Epubl ahead of print].
Voigt B, Krug M, Schachtele C, Totzke F, Hilgeroth A
(2008) Probing novel 1-aza-9-oxafluorenes as selective
GSK-3beta inhibitors. ChemMedChem 3, 120-126.
Testard A, Loge C, Leger B, Robert JM, Lozach O,
Blairvacq M, Meijer L, Thiery V, Besson T (2006)
Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen
synthase kinase-3. Bioorg Med Chem Lett 16, 34193423.
Palomo V, Soteras I, Perez DI, Perez C, Gil C, Campillo
NE, Martinez A (2011) Exploring the binding sites of
glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities. J Med Chem 54,
8461-8470.
Palomo V, Perez DI, Perez C, Morales-Garcia JA, Soteras
I, Alonso-Gil S, Encinas A, Castro A, Campillo NE,
Perez-Castillo A, Gil C, Martinez A (2012) 5-imino1,2,4-thiadiazoles: First small molecules as substrate
competitive inhibitors of glycogen synthase kinase 3. J
Med Chem 55, 1645-1661.
Perez DI, Palomo V, Perez C, Gil C, Dans PD, Luque
FJ, Conde S, Martinez A (2011) Switching reversibility
to irreversibility in glycogen synthase kinase 3 inhibitors:
Clues for specific design of new compounds. J Med Chem
54, 4042-4056.
Perez DI, Pistolozzi M, Palomo V, Redondo M, Fortugno C, Gil C, Felix G, Martinez A, Bertucci C (2012)
5-Imino-1,2-4-thiadiazoles and quinazolines derivatives
as glycogen synthase kinase 3beta (GSK-3beta) and
phosphodiesterase 7 (PDE7) inhibitors: Determination of
blood-brain barrier penetration and binding to human
serum albumin. Eur J Pharm Sci 45, 677-684.
Khanfar MA, Hill RA, Kaddoumi A, El Sayed KA (2010)
Discovery of novel GSK-3beta inhibitors with potent in
vitro and in vivo activities and excellent brain permeability
using combined ligand- and structure-based virtual screening. J Med Chem 53, 8534-8545.
Ibrahim N, Mouawad L, Legraverend M (2010) Novel 8arylated purines as inhibitors of glycogen synthase kinase.
Eur J Med Chem 45, 3389-3393.
Zou H, Zhou L, Li Y, Cui Y, Zhong H, Pan Z, Yang Z,
Quan J (2010) Benzo[e]isoindole-1,3-diones as potential
inhibitors of glycogen synthase kinase-3 (GSK-3). Synthesis, kinase inhibitory activity, zebrafish phenotype, and
modeling of binding mode. J Med Chem 53, 994-1003.
Sondhi SM, Singh N, Kumar A, Lozach O, Meijer L (2006)
Synthesis, anti-inflammatory, analgesic and kinase (CDK1, CDK-5 and GSK-3) inhibition activity evaluation of
benzimidazole/benzoxazole derivatives and some Schiff’s
bases. Bioorg Med Chem 14, 3758-3765.
Kim HJ, Choo H, Cho YS, No KT, Pae AN (2008) Novel
GSK-3beta inhibitors from sequential virtual screening.
Bioorg Med Chem 16, 636-643.
Zhou X, Zhou J, Li X, Guo C, Fang T, Chen Z (2011)
GSK-3beta inhibitors suppressed neuroinflammation in rat
cortex by activating autophagy in ischemic brain injury.
Biochem Biophys Res Commun 411, 271-275.
Caballero J, Zilocchi S, Tiznado W, Collina S, Rossi D
(2011) Binding studies and quantitative structure-activity
relationship of 3-amino-1H-indazoles as inhibitors of
GSK3beta. Chem Biol Drug Des 78, 631-641.
Lo Monte F, Kramer T, Gu J, Anumala UR, Marinelli L, La
Pietra V, Novellino V, Franco E, Demedts B, Van Leuven
D, Fuertes F, Dominguez A, Plotkin JM, Eldar-Finkelman
[1327]
[1328]
[1329]
[1330]
[1331]
[1332]
[1333]
[1334]
[1335]
[1336]
[1337]
[1338]
[1339]
[1340]
[1341]
645
B, Schmidt H, B (2012) Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen
synthase kinase-3alpha. J Med Chem 55, 4407-4424.
Rother M, Kittner B, Rudolphi K, Rossner M, Labs KH
(1996) HWA 285 (propentofylline) – a new compound for
the treatment of both vascular dementia and dementia of
the Alzheimer type. Ann N Y Acad Sci 777, 404-409.
Rother M, Erkinjuntti T, Roessner M, Kittner B, Marcusson J, Karlsson I (1998) Propentofylline in the treatment
of Alzheimer’s disease and vascular dementia: A review
of phase III trials. Dement Geriatr Cogn Disord 9(Suppl
1), 36-43.
Mielke R, Ghaemi M, Kessler J, Kittner B, Szelies B,
Herholz K, Heiss WD (1998) Propentofylline enhances
cerebral metabolic response to auditory memory stimulation in Alzheimer’s disease. J Neurol Sci 154, 76-82.
Mielke R, Moller HJ, Erkinjuntti T, Rosenkranz B,
Rother M, Kittner B (1998) Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia:
Overview of phase I and phase II clinical trials. Alzheimer
Dis Assoc Disord 12(Suppl 2), S29-S35.
Kittner B (1999) Clinical trials of propentofylline in vascular dementia. European/Canadian Propentofylline Study
Group. Alzheimer Dis Assoc Disord 13(Suppl 3), S166S171.
Chauhan NB, Siegel GJ, Feinstein DL (2005)
Propentofylline attenuates tau hyperphosphorylation in Alzheimer’s Swedish mutant model Tg2576.
Neuropharmacology 48, 93-104.
Hu S, Begum AN, Jones MR, Oh MS, Beech WK, Beech
BH, Yang F, Chen P, Ubeda OJ, Kim PC, Davies P,
Ma Q, Cole GM, Frautschy SA (2009) GSK3 inhibitors
show benefits in an Alzheimer’s disease (AD) model of
neurodegeneration but adverse effects in control animals.
Neurobiol Dis 33, 193-206.
Komsuoglu-Celikyurt I, Gocmez SS, Mutlu O, Gacar N,
Aricioglu F, Utkan T (2011) Evidence for the involvement
of neuronal nitric oxide synthase and soluble guanylate
cyclase on cognitive functions in rats. Life Sci 89, 905-910.
Thatcher GR, Bennett BM, Reynolds JN (2005) Nitric
oxide mimetic molecules as therapeutic agents in
Alzheimer’s disease. Curr Alzheimer Res 2, 171-182.
Qin Z, Luo J, Vandevrede L, Tavassoli E, Fa’ M, Teich AF,
Arancio O, Thatcher GR (2012) Design and synthesis of
neuroprotective methylthiazoles and modification as NOchimeras for neurodegenerative therapy. J Med Chem 55,
6784-6801.
Smith S, Dringenberg HC, Bennett BM, Thatcher GR,
Reynolds JN (2000) A novel nitrate ester reverses the cognitive impairment caused by scopolamine in the Morris
water maze. Neuroreport 11, 3883-3886.
Reynolds JN, Bennett BM, Boegman RJ, Jhamandas K,
Ratz JD, Zavorin SI, Scutaru D, Dumitrascu A, Thatcher
GR (2002) Neuroprotection against ischemic brain injury
conferred by a novel nitrate ester. Bioorg Med Chem Lett
12, 2863-2866.
Thatcher GR, Bennett BM, Dringenberg HC, Reynolds
JN (2004) Novel nitrates as NO mimetics directed at
Alzheimer’s disease. J Alzheimers Dis 6, S75-S84.
Thatcher GR, Bennett BM, Reynolds JN (2006) NO
chimeras as therapeutic agents in Alzheimer’s disease.
Curr Alzheimer Res 3, 237-245.
Bennett BM, Reynolds JN, Prusky GT, Douglas RM,
Sutherland RJ, Thatcher GR (2007) Cognitive deficits in
rats after forebrain cholinergic depletion are reversed by a
646
[1342]
[1343]
[1344]
[1345]
[1346]
[1347]
[1348]
[1349]
[1350]
[1351]
[1352]
[1353]
[1354]
[1355]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
novel NO mimetic nitrate ester. Neuropsychopharmacology 32, 505-513.
Schipper HM, Bennett DA, Liberman A, Bienias JL,
Schneider JA, Kelly J, Arvanitakis Z (2006) Glial heme
oxygenase-1 expression in Alzheimer disease and mild
cognitive impairment. Neurobiol Aging 27, 252-261.
Schipper HM (2007) Biomarker potential of heme
oxygenase-1 in Alzheimer’s disease and mild cognitive
impairment. Biomark Med 1, 375-385.
Schipper HM (2011) Heme oxygenase-1 in Alzheimer disease: A tribute to Moussa Youdim. J Neural Transm 118,
381-387.
Hascalovici JR, Vaya J, Khatib S, Holcroft CA, Zukor
H, Song W, Arvanitakis Z, Bennett DA, Schipper HM
(2009) Brain sterol dysregulation in sporadic AD and
MCI: Relationship to heme oxygenase-1. J Neurochem
110, 1241-1253.
Hascalovici JR, Song W, Vaya J, Khatib S, Fuhrman
B, Aviram M, Schipper HM (2009) Impact of heme
oxygenase-1 on cholesterol synthesis, cholesterol efflux
and oxysterol formation in cultured astroglia. J Neurochem
108, 72-81.
Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010)
Targeting the correct HDAC(s) to treat cognitive disorders.
Trends Pharmacol Sci 31, 605-617.
Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT
(2009) Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32, 591-601.
Zhang L, Sheng S, Qin C (2012) The role of HDAC6 in
Alzheimer’s disease. J Alzheimers Dis, doi: 10.3233/JAD2012-120727 [Epubl ahead of print].
Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A
(2012) Loss of HDAC5 impairs memory function: Implications for Alzheimer’s disease. J Alzheimers Dis, doi:
10.3233/JAD-2012-121009 [Epubl ahead of print].
Vaisburg A, Bernstein N, Frechette S, Allan M, AbouKhalil E, Leit S, Moradei O, Bouchain G, Wang J, Woo
SH, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A,
Beaulieu C, Li Z, Macleod AR, Besterman JM, Delorme
D (2004) (2-amino-phenyl)-amides of omega-substituted
alkanoic acids as new histone deacetylase inhibitors.
Bioorg Med Chem Lett 14, 283-287.
Vaisburg A, Paquin I, Bernstein N, Frechette S, Gaudette F,
Leit S, Moradei O, Raeppel S, Zhou N, Bouchain G, Woo
SH, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, TrachyBourget MC, Robert MF, Lu A, Yuk J, Rahil J, Macleod
AR, Besterman JM, Li Z, Delorme D (2007) N-(2-Aminophenyl)-4-(heteroarylmethyl)-benzamides as new histone
deacetylase inhibitors. Bioorg Med Chem Lett 17, 67296733.
Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A,
Frechilla D, Del RJ, Garcia-Osta A (2009) Phenylbutyrate
ameliorates cognitive deficit and reduces tau pathology in
an Alzheimer’s disease mouse model. Neuropsychopharmacology 34, 1721-1732.
Ricobaraza A, Cuadrado-Tejedor M, Garcia-Osta A (2011)
Long-term phenylbutyrate administration prevents memory deficits in Tg2576 mice by decreasing Abeta. Front
Biosci (Elite Ed) 3, 1375-1384.
Ricobaraza A, Cuadrado-Tejedor M, Marco S, PerezOtano I, Garcia-Osta A (2012) Phenylbutyrate rescues
dendritic spine loss associated with memory deficits in
a mouse model of Alzheimer disease. Hippocampus 22,
1040-1050.
[1356]
[1357]
[1358]
[1359]
[1360]
[1361]
[1362]
[1363]
[1364]
[1365]
[1366]
[1367]
[1368]
[1369]
[1370]
[1371]
Wiley JC, Pettan-Brewer C, Ladiges WC (2011) Phenylbutyric acid reduces amyloid plaques and rescues cognitive
behavior in AD transgenic mice. Aging Cell 10, 418-428.
Cuadrado-Tejedor M, Garcia-Osta A, Ricobaraza A,
Oyarzabal J, Franco R (2011) Defining the mechanism of
action of 4-phenylbutyrate to develop a small-moleculebased therapy for Alzheimer’s disease. Curr Med Chem
18, 5545-5553.
Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao
WN, Nieland TJ, Guan JS, Groves Kuhnle CE, Tang W,
Barker DD, Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ (2013) Crebinostat: A novel cognitive enhancer
that inhibits histone deacetylase activity and modulates
chromatin-mediated neuroplasticity. Neuropharmacology
61, 81-96.
Lu J, Yang C, Chen M, Ye DY, Lonser RR, Brady RO,
Zhuang Z (2011) Histone deacetylase inhibitors prevent
the degradation and restore the activity of glucocerebrosidase in Gaucher disease. Proc Natl Acad Sci U S A 108,
21200-21205.
Kozikowski AP, Chen Y, Subhasish T, Lewin NE, Blumberg PM, Zhong Z, D’Annibale MA, Wang WL, Shen Y,
Langley B (2009) Searching for disease modifiers-PKC
activation and HDAC inhibition – a dual drug approach to
Alzheimer’s disease that decreases Abeta production while
blocking oxidative stress. ChemMedChem 4, 1095-1105.
Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer
RA (2009) Midlife serum cholesterol and increased risk
of Alzheimer’s and vascular dementia three decades later.
Dement Geriatr Cogn Disord 28, 75-80.
Solomon A, Kivipelto M (2009) Cholesterol-modifying
strategies for Alzheimer’s disease. Expert Rev Neurother
9, 695-709.
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA
(2000) Statins and the risk of dementia. Lancet 356, 16271631.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel
G (2000) Decreased prevalence of Alzheimer disease
associated with 3-hydroxy-3-methyglutaryl coenzyme A
reductase inhibitors. Arch Neurol 57, 1439-1443.
Wolozin B, Manger J, Bryant R, Cordy J, Green RC,
McKee A (2006) Re-assessing the relationship between
cholesterol, statins and Alzheimer’s disease. Acta Neurol
Scand Suppl 185, 63-70.
Rockwood K, Kirkland S, Hogan DB, MacKnight C,
Merry H, Verreault R, Wolfson C, McDowell I (2002)
Use of lipid-lowering agents, indication bias, and the risk
of dementia in community-dwelling elderly people. Arch
Neurol 59, 223-227.
Rockwood K (2006) Epidemiological and clinical trials
evidence about a preventive role for statins in Alzheimer’s
disease. Acta Neurol Scand Suppl 185, 71-77.
Doraiswamy PM (2002) Non-cholinergic strategies for
treating and preventing Alzheimer’s disease. CNS Drugs
16, 811-824.
Whitfield JF (2006) Can statins put the brakes on
Alzheimer’s disease? Expert Opin Investig Drugs 15,
1479-1485.
Sparks DL (2011) Alzheimer disease: Statins in the treatment of Alzheimer disease. Nat Rev Neurol 7, 662-663.
Pac-Soo C, Lloyd DG, Vizcaychipi MP, Ma D (2011)
Statins: The role in the treatment and prevention of
Alzheimer’s neurodegeneration. J Alzheimers Dis 27, 110.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1372]
[1373]
[1374]
[1375]
[1376]
[1377]
[1378]
[1379]
[1380]
[1381]
[1382]
[1383]
[1384]
[1385]
Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: I. Review of
epidemiological and preclinical studies. Arch Neurol 68,
1239-1244.
Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: II. Review
of human trials and recommendations. Arch Neurol 68,
1385-1392.
Pani A, Mandas A, Dessi S (2010) Cholesterol,
Alzheimer’s disease, prion disorders: A menage a trois?
Curr Drug Targets 11, 1018-1031.
Sabbagh MN, Sparks DL (2012) Statins to treat
Alzheimer’s disease: An incomplete story. Expert Rev
Neurother 12, 27-30.
Gamba P, Testa G, Sottero B, Gargiulo S, Poli G, Leonarduzzi G (2012) The link between altered cholesterol
metabolism and Alzheimer’s disease. Ann N Y Acad Sci
1259, 54-64.
Bettermann K, Arnold AM, Williamson J, Rapp S, Sink
K, Toole JF, Carlson MC, Yasar S, Dekosky S, Burke GL
(2012) Statins, risk of dementia, and cognitive function:
Secondary analysis of the ginkgo evaluation of memory
study. J Stroke Cerebrovasc Dis 21, 436-444.
Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von BK,
Hennerici M, Beyreuther K, Hartmann T (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta
-amyloid peptides Abeta 42 and Abeta 40 in vitro and in
vivo. Proc Natl Acad Sci U S A 98, 5856-5861.
Tong XK, Nicolakakis N, Fernandes P, Ongali B, Brouillette J, Quirion R, Hamel E (2009) Simvastatin improves
cerebrovascular function and counters soluble amyloidbeta, inflammation and oxidative stress in aged APP mice.
Neurobiol Dis 35, 406-414.
Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo
L, Buxbaum JD, Bogush A, Petanceska S, Gandy S
(2004) Atorvastatin-induced activation of Alzheimer’s
alpha secretase is resistant to standard inhibitors of protein
phosphorylation-regulated ectodomain shedding. J Neurochem 90, 1005-1010.
Piermartiri TC, Figueiredo CP, Rial D, Duarte FS,
Bezerra SC, Mancini G, de Bem AF, Prediger RD,
Tasca CI (2010) Atorvastatin prevents hippocampal cell
death, neuroinflammation and oxidative stress following
amyloid-beta(1-40) administration in mice: Evidence for
dissociation between cognitive deficits and neuronal damage. Exp Neurol 226, 274-284.
Xiu J, Nordberg A, Shan KR, Yu WF, Olsson JM, Nordman
T, Mousavi M, Guan ZZ (2005) Lovastatin stimulates upregulation of alpha7 nicotinic receptors in cultured neurons
without cholesterol dependency, a mechanism involving
production of the alpha-form of secreted amyloid precursor protein. J Neurosci Res 82, 531-541.
Xiu J, Nordberg A, Qi X, Guan ZZ (2006) Influence of
cholesterol and lovastatin on alpha-form of secreted amyloid precursor protein and expression of alpha7 nicotinic
receptor on astrocytes. Neurochem Int 49, 459-465.
Si ML, Long C, Yang DI, Chen MF, Lee TJ (2005) Statins
prevent beta-amyloid inhibition of sympathetic alpha7nAChR-mediated nitrergic neurogenic dilation in porcine
basilar arteries. J Cereb Blood Flow Metab 25, 15731585.
Mozayan M, Lee TJ (2007) Statins prevent cholinesterase
inhibitor blockade of sympathetic alpha7-nAChRmediated currents in rat superior cervical ganglion
[1386]
[1387]
[1388]
[1389]
[1390]
[1391]
[1392]
[1393]
[1394]
[1395]
[1396]
[1397]
[1398]
647
neurons. Am J Physiol Heart Circ Physiol 293,
H1737-H1744.
Sharma B, Singh N, Singh M (2008) Modulation
of celecoxib- and streptozotocin-induced experimental
dementia of Alzheimer’s disease by pitavastatin and
donepezil. J Psychopharmacol 22, 162-171.
Kurata T, Miyazaki K, Kozuki M, Panin VL, Morimoto
N, Ohta Y, Nagai M, Ikeda Y, Matsuura T, Abe K (2011)
Atorvastatin and pitavastatin improve cognitive function
and reduce senile plaque and phosphorylated tau in aged
APP mice. Brain Res 1371, 161-170.
Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y,
Ikeda Y, Abe K (2012) Atorvastatin and pitavastatin reduce
senile plaques and inflammatory responses in a mouse
model of Alzheimer’s disease. Neurol Res 34, 601-610.
Bernick C, Katz R, Smith NL, Rapp S, Bhadelia R, Carlson
M, Kuller L (2005) Statins and cognitive function in the
elderly: The Cardiovascular Health Study. Neurology 65,
1388-1394.
Winblad B, Jelic V, Kershaw P, Amatniek J (2007)
Effects of statins on cognitive function in patients with
Alzheimer’s disease in galantamine clinical trials. Drugs
Aging 24, 57-61.
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer
LJ, Browne P, Wasser D, Johnson-Traver S, Lochhead J,
Ziolwolski C (2005) Atorvastatin for the treatment of mild
to moderate Alzheimer disease: Preliminary results. Arch
Neurol 62, 753-757.
Sparks DL, Sabbagh MN, Connor DJ, Lopez J, Launer
LJ, Petanceska S, Browne P, Wassar D, Johnson-Traver
S, Lochhead J, Ziolkowski C (2005) Atorvastatin therapy lowers circulating cholesterol but not free radical
activity in advance of identifiable clinical benefit in the
treatment of mild-to-moderate AD. Curr Alzheimer Res 2,
343-353.
Sparks DL, Connor DJ, Sabbagh MN, Petersen RB,
Lopez J, Browne P (2006) Circulating cholesterol levels,
apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer’s
disease: Results of the Alzheimer’s Disease CholesterolLowering Treatment (ADCLT) trial. Acta Neurol Scand
Suppl 185, 3-7.
Jones RW, Kivipelto M, Feldman H, Sparks L, Doody
R, Waters DD, Hey-Hadavi J, Breazna A, Schindler
RJ, Ramos H (2008) The Atorvastatin/Donepezil in
Alzheimer’s Disease Study (LEADe): Design and baseline
characteristics. Alzheimers Dement 4, 145-153.
Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters
DD, Jones RW, Schwam E, Schindler R, Hey-Hadavi J,
DeMicco DA, Breazna A (2010) Randomized controlled
trial of atorvastatin in mild to moderate Alzheimer disease:
LEADe. Neurology 74, 956-964.
Trompet S, van VP, de Craen AJ, Jolles J, Buckley BM,
Murphy MB, Ford I, Macfarlane PW, Sattar N, Packard CJ,
Stott DJ, Shepherd J, Bollen EL, Blauw GJ, Jukema JW,
Westendorp RG (2010) Pravastatin and cognitive function
in the elderly. Results of the PROSPER study. J Neurol
257, 85-90.
Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van
Dyck CH, Aisen PS (2011) A randomized, double-blind,
placebo-controlled trial of simvastatin to treat Alzheimer
disease. Neurology 77, 556-563.
Sjogren M, Gustafsson K, Syversen S, Olsson A, Edman A,
Davidsson P, Wallin A, Blennow K (2003) Treatment with
simvastatin in patients with Alzheimer’s disease lowers
648
[1399]
[1400]
[1401]
[1402]
[1403]
[1404]
[1405]
[1406]
[1407]
[1408]
[1409]
[1410]
[1411]
[1412]
[1413]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
both alpha- and beta-cleaved amyloid precursor protein.
Dement Geriatr Cogn Disord 16, 25-30.
Hoglund K, Syversen S, Lewczuk P, Wallin A, Wiltfang J,
Blennow K (2005) Statin treatment and a disease-specific
pattern of beta-amyloid peptides in Alzheimer’s disease.
Exp Brain Res 164, 205-214.
Hoglund K, Thelen KM, Syversen S, Sjogren M, von BK,
Wallin A, Vanmechelen E, Vanderstichele H, Lutjohann
D, Blennow K (2005) The effect of simvastatin treatment
on the amyloid precursor protein and brain cholesterol
metabolism in patients with Alzheimer’s disease. Dement
Geriatr Cogn Disord 19, 256-265.
Hoglund K, Wallin A, Blennow K (2006) Effect of statins
on beta-amyloid metabolism in humans: Potential importance for the development of senile plaques in Alzheimer’s
disease. Acta Neurol Scand Suppl 185, 87-92.
Hoglund K, Blennow K (2007) Effect of HMG-CoA
reductase inhibitors on beta-amyloid peptide levels: Implications for Alzheimer’s disease. CNS Drugs 21, 449462.
Carlsson CM, Gleason CE, Hess TM, Moreland KA,
Blazel HM, Koscik RL, Schreiber NT, Johnson SC,
Atwood CS, Puglielli L, Hermann BP, McBride PE, Stein
JH, Sager MA, Asthana S (2008) Effects of simvastatin on
cerebrospinal fluid biomarkers and cognition in middleaged adults at risk for Alzheimer’s disease. J Alzheimers
Dis 13, 187-197.
Mans RA, Chowdhury N, Cao D, McMahon LL, Li
L (2010) Simvastatin enhances hippocampal long-term
potentiation in C57BL/6 mice. Neuroscience 166, 435444.
Mans RA, McMahon LL, Li L (2012) Simvastatinmediated enhancement of long-term potentiation is driven
by farnesyl-pyrophosphate depletion and inhibition of farnesylation. Neuroscience 202, 1-9.
Mans RA, McMahon LL, Li L (2012) Molecular mechanisms for simvastatin-mediated enhancement of synaptic
plasticity. Mol Neurodegener 7(Suppl 1), O4.
Campoy S, Sierra S, Suarez B, Ramos MC, Velasco J,
Burgos JS, Adrio JL (2010) Semisynthesis of novel
monacolin J derivatives: Hypocholesterolemic and neuroprotective activities. J Antibiot (Tokyo) 63, 499-505.
Messier C, Teutenberg K (2005) The role of insulin, insulin
growth factor, and insulin-degrading enzyme in brain aging
and Alzheimer’s disease. Neural Plast 12, 311-328.
Zhao Z, Xiang Z, Haroutunian V, Buxbaum JD, Stetka
B, Pasinetti GM (2007) Insulin degrading enzyme activity selectively decreases in the hippocampal formation of
cases at high risk to develop Alzheimer’s disease. Neurobiol Aging 28, 824-830.
Wang S, Wang R, Chen L, Bennett DA, Dickson DW,
Wang DS (2010) Expression and functional profiling
of neprilysin, insulin-degrading enzyme, and endothelinconverting enzyme in prospectively studied elderly and
Alzheimer’s brain. J Neurochem 115, 47-57.
Liu Z, Zhu H, Fang GG, Walsh K, Mwamburi M, Wolozin
B, bdul-Hay SO, Ikezu T, Leissring MA, Qiu WQ (2012)
Characterization of insulin degrading enzyme and other
amyloid-beta degrading proteases in human serum: A role
in Alzheimer’s disease? J Alzheimers Dis 29, 329-340.
Savage MJ, Gingrich DE (2009) Advances in the development of kinase inhibitor therapeutics for Alzheimer’s
disease. Drug Dev Res 70, 125-144.
Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang
JZ, Zhu LQ (2011) Acetyl-L-carnitine ameliorates spatial
[1414]
[1415]
[1416]
[1417]
[1418]
[1419]
[1420]
[1421]
[1422]
[1423]
[1424]
[1425]
memory deficits induced by inhibition of phosphoinositol3 kinase and protein kinase C. J Neurochem 118, 864878.
Filiz G, Caragounis A, Bica L, Du T, Masters CL,
Crouch PJ, White AR (2008) Clioquinol inhibits
peroxide-mediated toxicity through up-regulation of
phosphoinositol-3-kinase and inhibition of p53 activity.
Int J Biochem Cell Biol 40, 1030-1042.
Piette F, Belmin J, Vincent H, Schmidt N, Pariel S,
Verny M, Marquis C, Mely J, Hugonot-Diener L, Kinet
JP, Dubreuil P, Moussy A, Hermine O (2011) Masitinib
as an adjunct therapy for mild-to-moderate Alzheimer’s
disease: A randomised, placebo-controlled phase 2 trial.
Alzheimers Res Ther 3, 16.
Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M,
Casteran N, Borge L, Hajem B, Lermet A, Sippl W, Voisset E, Arock M, Auclair C, Leventhal PS, Mansfield CD,
Moussy A, Hermine O (2009) Masitinib (AB1010), a
potent and selective tyrosine kinase inhibitor targeting
KIT. PLoS One 4, e7258.
MacGregor DG, Mallon AP, Harvey AL, Young L,
Nimmo HG, Stone TW (2007) Group S8A serine
proteases, including a novel enzyme cadeprin, induce
long-lasting, metabotropic glutamate receptor-dependent
synaptic depression in rat hippocampal slices. Eur J Neurosci 26, 1870-1880.
Ramsden N, Perrin J, Ren Z, Lee BD, Zinn N, Dawson VL,
Tam D, Bova M, Lang M, Drewes G, Bantscheff M, Bard
F, Dawson TM, Hopf C (2011) Chemoproteomics-based
design of potent LRRK2-selective lead compounds that
attenuate Parkinson’s disease-related toxicity in human
neurons. ACS Chem Biol 6, 1021-1028.
Dhawan G, Combs CK (2012) Inhibition of Src kinase
activity attenuates amyloid associated microgliosis in a
murine model of Alzheimer’s disease. J Neuroinflammation 9, 117.
Huentelman MJ, Stephan DA, Talboom J, Corneveaux
JJ, Reiman DM, Gerber JD, Barnes CA, Alexander GE,
Reiman EM, Bimonte-Nelson HA (2009) Peripheral delivery of a ROCK inhibitor improves learning and working
memory. Behav Neurosci 123, 218-223.
Schneider A, Huentelman MJ, Kremerskothen J, Duning
K, Spoelgen R, Nikolich K (2010) KIBRA: A new gateway
to learning and memory? Front Aging Neurosci 2, 4.
Castro-Alvarez JF, Gutierrez-Vargas J, Darnaudery M,
Cardona-Gomez GP (2011) ROCK inhibition prevents tau
hyperphosphorylation and p25/CDK5 increase after global
cerebral ischemia. Behav Neurosci 125, 465-472.
Corneveaux JJ, Liang WS, Reiman EM, Webster JA,
Myers AJ, Zismann VL, Joshipura KD, Pearson JV, HuLince D, Craig DW, Coon KD, Dunckley T, Bandy D, Lee
W, Chen K, Beach TG, Mastroeni D, Grover A, Ravid R,
Sando SB, Aasly JO, Heun R, Jessen F, Kolsch H, Rogers
J, Hutton ML, Melquist S, Petersen RC, Alexander GE,
Caselli RJ, Papassotiropoulos A, Stephan DA, Huentelman
MJ (2010) Evidence for an association between KIBRA
and late-onset Alzheimer’s disease. Neurobiol Aging 31,
901-909.
Hofmann SG, Smits JA, Asnaani A, Gutner CA, Otto MW
(2011) Cognitive enhancers for anxiety disorders. Pharmacol Biochem Behav 99, 275-284.
Liu M, Poulose S, Schuman E, Zaitsev AD, Dobson B,
Auerbach K, Seyb K, Cuny GD, Glicksman MA, Stein RL,
Yue Z (2010) Development of a mechanism-based highthroughput screen assay for leucine-rich repeat kinase
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1426]
[1427]
[1428]
[1429]
[1430]
[1431]
[1432]
[1433]
[1434]
[1435]
[1436]
[1437]
[1438]
2–discovery of LRRK2 inhibitors. Anal Biochem 404, 186192.
Chen H, Chan BK, Drummond J, Estrada AA, GunznerToste J, Liu X, Liu Y, Moffat J, Shore D, Sweeney ZK, Tran
T, Wang S, Zhao G, Zhu H, Burdick DJ (2012) Discovery
of selective LRRK2 inhibitors guided by computational
analysis and molecular modeling. J Med Chem 55, 55365545.
Echeverria V, Burgess S, Gamble-George J, Zeitlin R, Lin
X, Cao C, Arendash GW (2009) Sorafenib inhibits nuclear
factor kappa B, decreases inducible nitric oxide synthase
and cyclooxygenase-2 expression, and restores working memory in APPswe mice. Neuroscience 162, 12201231.
Echeverria V, Burgess S, Gamble-George J, Arendash GW,
Citron BA (2008) Raf inhibition protects cortical cells
against beta-amyloid toxicity. Neurosci Lett 444, 92-96.
Gingras K, Avedissian H, Thouin E, Boulanger V,
Essagian C, McKerracher L, Lubell WD (2004)
Synthesis and evaluation of 4-(1-aminoalkyl)-N(4-pyridyl)cyclohexanecarboxamides as Rho kinase
inhibitors and neurite outgrowth promoters. Bioorg Med
Chem Lett 14, 4931-4934.
Page TH, Brown A, Timms EM, Foxwell BM, Ray KP
(2010) Inhibitors of p38 suppress cytokine production in
rheumatoid arthritis synovial membranes: Does variable
inhibition of interleukin-6 production limit effectiveness
in vivo? Arthritis Rheum 62, 3221-3231.
Baran H, Jellinger K, Deecke L (1999) Kynurenine
metabolism in Alzheimer’s disease. J Neural Transm 106,
165-181.
Potter MC, Elmer GI, Bergeron R, Albuquerque EX,
Guidetti P, Wu HQ, Schwarcz R (2010) Reduction of
endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive
behavior. Neuropsychopharmacology 35, 1734-1742.
Rossi F, Valentina C, Garavaglia S, Sathyasaikumar KV,
Schwarcz R, Kojima S, Okuwaki K, Ono S, Kajii Y,
Rizzi M (2010) Crystal structure-based selective targeting
of the pyridoxal 5 -phosphate dependent enzyme kynurenine aminotransferase II for cognitive enhancement. J Med
Chem 53, 5684-5689.
Dounay AB, Anderson M, Vechle BM, Campbell BM,
Claffey MM, Evdokimov A, Evrard E, Fonseca KR, Gan
XM, Ghosh S, Hayward MM, Horner W, Kim JY, McAllister LA, Pandit J, Paradis V, Parikh VD, Reese MR, Rong S,
Salafia MA, Schuyten K, Strick CA, Tuttle JB, Valentine J,
Wang H, Zawadzke LE, Verhoest PR (2012) Discovery of
brain-penetrant, irreversible kynurenine aminotransferase
II inhibitors for schizophrenia. ACS Med Chem Lett 3,
187-192.
Radmark O, Werz O, Steinhilber D, Samuelsson B (2007)
5-Lipoxygenase: Regulation of expression and enzyme
activity. Trends Biochem Sci 32, 332-341.
Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Pratico D
(2008) 5-Lipoxygenase gene disruption reduces amyloidbeta pathology in a mouse model of Alzheimer’s disease.
FASEB J 22, 1169-1178.
Chu J, Pratico D (2011) 5-lipoxygenase as an endogenous
modulator of amyloid beta formation in vivo. Ann Neurol
69, 34-46.
Chu J, Pratico D (2011) Pharmacologic blockade of
5-lipoxygenase improves the amyloidotic phenotype of an
Alzheimer’s disease transgenic mouse model involvement
of gamma-secretase. Am J Pathol 178, 1762-1769.
[1439]
[1440]
[1441]
[1442]
[1443]
[1444]
[1445]
[1446]
[1447]
[1448]
[1449]
[1450]
[1451]
[1452]
[1453]
[1454]
649
Hashimoto K (2011) Can minocycline prevent the onset of
Alzheimer’s disease? Ann Neurol 69, 739-740.
Song Y, Wei EQ, Zhang WP, Ge QF, Liu JR, Wang ML,
Huang XJ, Hu X, Chen Z (2006) Minocycline protects
PC12 cells against NMDA-induced injury via inhibiting
5-lipoxygenase activation. Brain Res 1085, 57-67.
Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS,
Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim
S, Suh YH (2007) Minocycline attenuates neuronal cell
death and improves cognitive impairment in Alzheimer’s
disease models. Neuropsychopharmacology 32, 23932404.
Burgos-Ramos E, Puebla-Jimenez L, rilla-Ferreiro E
(2008) Minocycline provides protection against betaamyloid(25-35)-induced alterations of the somatostatin
signaling pathway in the rat temporal cortex. Neuroscience
154, 1458-1466.
Burgos-Ramos E, Puebla-Jimenez L, rilla-Ferreiro
E (2009) Minocycline prevents Abeta(25-35)-induced
reduction of somatostatin and neprilysin content in rat
temporal cortex. Life Sci 84, 205-210.
Seabrook TJ, Jiang L, Maier M, Lemere CA (2006)
Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53, 776-782.
Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE (2007) Minocycline reduces
microglial activation and improves behavioral deficits in
a transgenic model of cerebral microvascular amyloid. J
Neurosci 27, 3057-3063.
Parachikova A, Vasilevko V, Cribbs DH, LaFerla FM,
Green KN (2010) Reductions in amyloid-beta-derived
neuroinflammation, with minocycline, restore cognition
but do not significantly affect tau hyperphosphorylation.
J Alzheimers Dis 21, 527-542.
Kreutzmann P, Wolf G, Kupsch K (2010) Minocycline
recovers MTT-formazan exocytosis impaired by amyloid
beta peptide. Cell Mol Neurobiol 30, 979-984.
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello
AC (2012) Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of
Alzheimer’s disease-like amyloid pathology. J Neuroinflammation 9, 62.
Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger
DP, Anderton BH (2009) Minocycline reduces the development of abnormal tau species in models of Alzheimer’s
disease. FASEB J 23, 739-750.
Noble W, Garwood CJ, Hanger DP (2009) Minocycline as
a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion 3, 78-83.
Garwood CJ, Cooper JD, Hanger DP, Noble W (2010)
Anti-inflammatory impact of minocycline in a mouse
model of tauopathy. Front Psychiatr 1, 136.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling
J, Richardson P, Dursun S, Dunn G, Deakin B
(2012) Minocycline benefits negative symptoms in
early schizophrenia: A randomised double-blind placebocontrolled clinical trial in patients on standard treatment.
J Psychopharmacol 26, 1185-1193.
Hieke M, Rodl CB, Wisniewska JM, la BE, Stark
H, Schubert-Zsilavecz M, Steinhilber D, Hofmann
B, Proschak E (2012) SAR-study on a new
class of imidazo[1,2-a]pyridine-based inhibitors of
5-lipoxygenase. Bioorg Med Chem Lett 22, 1969-1975.
Pisani L, Catto M, Leonetti F, Nicolotti O, Stefanachi A,
Campagna F, Carotti A (2011) Targeting monoamine oxi-
650
[1455]
[1456]
[1457]
[1458]
[1459]
[1460]
[1461]
[1462]
[1463]
[1464]
[1465]
[1466]
[1467]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
dases with multipotent ligands: An emerging strategy in
the search of new drugs against neurodegenerative diseases. Curr Med Chem 18, 4568-4587.
Carradori S, Secci D, Bolasco A, Chimenti P, D’Ascenzio
M (2012) Patent-related survey on new monoamine oxidase inhibitors and their therapeutic potential. Expert Opin
Ther Pat 22, 759-801.
Kennedy BP, Ziegler MG, Alford M, Hansen LA, Thal
LJ, Masliah E (2003) Early and persistent alterations in
prefrontal cortex MAO A and B in Alzheimer’s disease. J
Neural Transm 110, 789-801.
Gotz ME, Fischer P, Gsell W, Riederer P, Streifler M,
Simanyi M, Muller F, Danielczyk W (1998) Platelet
monoamine oxidase B activity in dementia. A 4-year
follow-up. Dement Geriatr Cogn Disord 9, 74-77.
Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik
ZI, Warshawsky A, Youdim MB, Fridkin M (2005)
Design, synthesis, and evaluation of novel bifunctional
iron-chelators as potential agents for neuroprotection in
Alzheimer’s, Parkinson’s, and other neurodegenerative
diseases. Bioorg Med Chem 13, 773-783.
Gal S, Fridkin M, Amit T, Zheng H, Youdim MB (2006)
M30, a novel multifunctional neuroprotective drug with
potent iron chelating and brain selective monoamine
oxidase-ab inhibitory activity for Parkinson’s disease. J
Neural Transm Suppl 70, 447-456.
Youdim MB (2006) The path from anti Parkinson drug
selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr
Alzheimer Res 3, 541-550.
Avramovich-Tirosh Y, Amit T, Bar-Am O, Zheng H,
Fridkin M, Youdim MB (2007) Therapeutic targets and
potential of the novel brain- permeable multifunctional
iron chelator-monoamine oxidase inhibitor drug, M-30,
for the treatment of Alzheimer’s disease. J Neurochem 100,
490-502.
Avramovich-Tirosh Y, Reznichenko L, Mit T, Zheng H,
Fridkin M, Weinreb O, Mandel S, Youdim MB (2007) Neurorescue activity, APP regulation and amyloid-beta peptide
reduction by novel multi-functional brain permeable ironchelating- antioxidants, M-30 and green tea polyphenol,
EGCG. Curr Alzheimer Res 4, 403-411.
Weinreb O, Mandel S, Bar-Am O, Amit T (2011)
Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic
agents for Alzheimer’s disease: A tribute to Moussa
Youdim. J Neural Transm 118, 479-492.
Johnson S, Tazik S, Lu D, Johnson C, Youdim MB, Wang
J, Rajkowska G, Ou XM (2010) The new inhibitor of
monoamine oxidase, M30, has a neuroprotective effect
against dexamethasone-induced brain cell apoptosis. Front
Neurosci 4, 180.
Zheng H, Fridkin M, Youdim MB (2010) Site-activated
chelators derived from anti-Parkinson drug rasagiline as a
potential safer and more effective approach to the treatment
of Alzheimer’s disease. Neurochem Res 35, 2117-2123.
Sterling J, Veinberg A, Lerner D, Goldenberg W, Levy
R, Youdim M, Finberg J (1998) (R)(+)-N-propargyl-1aminoindan (rasagiline) and derivatives: Highly selective
and potent inhibitors of monoamine oxidase B. J Neural
Transm Suppl 52, 301-305.
Youdim MB, Bar AO, Yogev-Falach M, Weinreb O,
Maruyama W, Naoi M, Amit T (2005) Rasagiline:
Neurodegeneration, neuroprotection, and mitochondrial
permeability transition. J Neurosci Res 79, 172-179.
[1468]
[1469]
[1470]
[1471]
[1472]
[1473]
[1474]
[1475]
[1476]
[1477]
[1478]
[1479]
[1480]
[1481]
[1482]
[1483]
Oldfield V, Keating GM, Perry CM (2007) Rasagiline: A
review of its use in the management of Parkinson’s disease.
Drugs 67, 1725-1747.
Oldfield V, Keating GM, Perry CM (2008) Spotlight on
rasagiline in Parkinson’s disease. CNS Drugs 22, 83-86.
Olanow CW, Hauser RA, Jankovic J, Langston W, Lang A,
Poewe W, Tolosa E, Stocchi F, Melamed E, Eyal E, Rascol
O (2008) A randomized, double-blind, placebo-controlled,
delayed start study to assess rasagiline as a disease modifying therapy in Parkinson’s disease (the ADAGIO study):
Rationale, design, and baseline characteristics. Mov Disord 23, 2194-2201.
Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic
J, Lang A, Langston W, Melamed E, Poewe W, Stocchi
F, Tolosa E (2009) A double-blind, delayed-start trial of
rasagiline in Parkinson’s disease. N Engl J Med 361, 12681278.
Mehta SH, Morgan JC, Sethi KD (2010) Does rasagiline
have a disease-modifying effect on Parkinson’s disease?
Curr Neurol Neurosci Rep 10, 413-416.
Chahine LM, Stern MB (2011) Rasagiline in Parkinson’s
disease. Int Rev Neurobiol 100, 151-168.
Perez-Lloret S, Rascol O (2011) Safety of rasagiline for
the treatment of Parkinson’s disease. Expert Opin Drug
Saf 10, 633-643.
Rascol O, Fitzer-Attas CJ, Hauser R, Jankovic J, Lang A,
Langston JW, Melamed E, Poewe W, Stocchi F, Tolosa E,
Eyal E, Weiss YM, Olanow CW (2011) A double-blind,
delayed-start trial of rasagiline in Parkinson’s disease (the
ADAGIO study): Prespecified and post-hoc analyses of the
need for additional therapies, changes in UPDRS scores,
and non-motor outcomes. Lancet Neurol 10, 415-423.
Silver DE, Buck PO (2011) Determining the efficacy of
rasagiline in reducing bradykinesia among Parkinson’s
disease patients: A review. Int J Neurosci 121, 485-489.
Tolosa E, Stern MB (2012) Efficacy, safety and tolerability
of rasagiline as adjunctive therapy in elderly patients with
Parkinson’s disease. Eur J Neurol 19, 258-264.
Weinreb O, Amit T, Riederer P, Youdim MB, Mandel
SA (2011) Neuroprotective profile of the multitarget drug
rasagiline in Parkinson’s disease. Int Rev Neurobiol 100,
127-149.
Hanagasi HA, Gurvit H, Unsalan P, Horozoglu H, Tuncer
N, Feyzioglu A, Gunal DI, Yener GG, Cakmur R, Sahin
HA, Emre M (2011) The effects of rasagiline on cognitive
deficits in Parkinson’s disease patients without dementia:
A randomized, double-blind, placebo-controlled, multicenter study. Mov Disord 26, 1851-1858.
Youdim MB, Maruyama W, Naoi M (2005) Neuropharmacological, neuroprotective and amyloid precursor
processing properties of selective MAO-B inhibitor
antiparkinsonian drug, rasagiline. Drugs Today (Barc ) 41,
369-391.
Wong FK, Lee SH, Atcha Z, Ong AB, Pemberton DJ, Chen
WS (2010) Rasagiline improves learning and memory in
young healthy rats. Behav Pharmacol 21, 278-282.
Leonetti F, Capaldi C, Pisani L, Nicolotti O, Muncipinto
G, Stefanachi A, Cellamare S, Caccia C, Carotti A (2007)
Solid-phase synthesis and insights into structure-activity
relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase. J Med Chem
50, 4909-4916.
Pevarello P, Bonsignori A, Dostert P, Heidempergher F,
Pinciroli V, Colombo M, McArthur RA, Salvati P, Post C,
Fariello RG, Varasi M (1998) Synthesis and anticonvulsant
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1484]
[1485]
[1486]
[1487]
[1488]
[1489]
[1490]
[1491]
[1492]
[1493]
[1494]
[1495]
[1496]
[1497]
[1498]
activity of a new class of 2-[(arylalky)amino]alkanamide
derivatives. J Med Chem 41, 579-590.
Zhang K, Xue N, Shi X, Liu W, Meng J, Du Y (2011)
A validated chiral liquid chromatographic method for the
enantiomeric separation of safinamide mesilate, a new
anti-Parkinson drug. J Pharm Biomed Anal 55, 220-224.
Strolin Benedetti MS, Marrari P, Colombo M, Castelli MG,
Arand M, Oesch F, Dostert P (1994) The anticonvulsant
FCE 26743 is a selective and short-acting MAO-B inhibitor
devoid of inducing properties towards cytochrome P450dependent testosterone hydroxylation in mice and rats. J
Pharm Pharmacol 46, 814-819.
Strolin Benedetti M, Tocchetti P, Rocchetti M, Martignoni
M, Marrari P, Poggesi I, Dostert P (1995) Enantioselective
recognition of two anticonvulsants, FCE 26743 and FCE
28073, by MAO, and relationship between MAO-B inhibition and FCE 26743 concentrations in rat brain. Prog
Brain Res 106, 123-134.
Fariello RG, McArthur RA, Bonsignori A, Cervini MA,
Maj R, Marrari P, Pevarello P, Wolf HH, Woodhead JW,
White HS, Varasi M, Salvati P, Post C (1998) Preclinical
evaluation of PNU-151774E as a novel anticonvulsant. J
Pharmacol Exp Ther 285, 397-403.
Chazot PL (2001) Safinamide (Newron Pharmaceuticals).
Curr Opin Investig Drugs 2, 809-813.
Chazot PL (2007) Safinamide for the treatment of Parkinson’s disease, epilepsy and restless legs syndrome. Curr
Opin Investig Drugs 8, 570-579.
Fariello RG (2007) Safinamide. Neurotherapeutics 4, 110116.
Onofrj M, Bonanni L, Thomas A (2008) An expert opinion
on safinamide in Parkinson’s disease. Expert Opin Investig
Drugs 17, 1115-1125.
Naoi M, Nomura Y, Ishiki R, Suzuki H, Nagatsu T (1988)
4-(O-benzylphenoxy)-N-methylbutylamine (bifemelane)
and other 4-(O-benzylphenoxy)-N-methylalkylamines as
new inhibitors of type A and B monoamine oxidase. J
Neurochem 50, 243-247.
Yoshida Y, Nakane A, Morita M, Kudo Y (2006) A novel
effect of bifemelane, a nootropic drug, on intracellular
Ca2+ levels in rat cerebral astrocytes. J Pharmacol Sci
100, 126-132.
Cesura AM, Galva MD, Imhof R, Kyburz E, Picotti GB,
Da PM (1989) [3H]Ro 19-6327: A reversible ligand and
affinity labelling probe for monoamine oxidase-B. Eur J
Pharmacol 162, 457-465.
Cesura AM, Borroni E, Gottowik J, Kuhn C, Malherbe P,
Martin J, Richards JG (1999) Lazabemide for the treatment of Alzheimer’s disease: Rationale and therapeutic
perspectives. Adv Neurol 80, 521-528.
Henriot S, Kuhn C, Kettler R, Da PM (1994) Lazabemide
(Ro 19-6327), a reversible and highly sensitive MAOB inhibitor: Preclinical and clinical findings. J Neural
Transm Suppl 41, 321-325.
Janssens de Varebeke P, Schallauer E, Rausch WD,
Riederer P, Youdim MB (1990) Milacemide, the selective substrate and enzyme-activated specific inhibitor of
monoamine oxidase B, increases dopamine but not serotonin in caudate nucleus of rhesus monkey. Neurochem Int
17, 325-329.
Dysken MW, Mendels J, LeWitt P, Reisberg B, Pomara
N, Wood J, Skare S, Fakouhi JD, Herting RL (1992)
Milacemide: A placebo-controlled study in senile dementia of the Alzheimer type. J Am Geriatr Soc 40, 503506.
[1499]
[1500]
[1501]
[1502]
[1503]
[1504]
[1505]
[1506]
[1507]
[1508]
[1508]
[1508]
[1509]
[1510]
[1511]
651
Finkelstein JE, Hengemihle JM, Ingram DK, Petri HL
(1994) Milacemide treatment in mice enhances acquisition of a Morris-type water maze task. Pharmacol Biochem
Behav 49, 707-710.
Dorfmueller HC, van Aalten DM (2010) Screening-based
discovery of drug-like O-GlcNAcase inhibitor scaffolds.
FEBS Lett 584, 694-700.
Dorfmueller HC, Borodkin VS, Blair DE, Pathak S,
Navratilova I, van Aalten DM (2011) Substrate and product analogues as human O-GlcNAc transferase inhibitors.
Amino Acids 40, 781-792.
Schimpl M, Schuttelkopf AW, Borodkin VS, van Aalten
DM (2010) Human OGA binds substrates in a conserved
peptide recognition groove. Biochem J 432, 1-7.
Gay LM, Zheng X, van Aalten DM (2011) Molecular
recognition: O-GlcNAc transfer: Size matters. Nat Chem
Biol 7, 134-135.
Jang H, Kim TW, Yoon S, Choi SY, Kang TW, Kim SY,
Kwon YW, Cho EJ, Youn HD (2012) O-GlcNAc regulates
pluripotency and reprogramming by directly acting on core
components of the pluripotency network. Cell Stem Cell
11, 62-74.
Dorfmueller HC, Borodkin VS, Schimpl M, Shepherd SM,
Shpiro NA, van Aalten DM (2006) GlcNAcstatin: A picomolar, selective O-GlcNAcase inhibitor that modulates
intracellular O-glcNAcylation levels. J Am Chem Soc 128,
16484-16485.
Dorfmueller HC, Borodkin VS, Schimpl M, van Aalten DM (2009) GlcNAcstatins are nanomolar inhibitors
of human O-GlcNAcase inducing cellular hyper-OGlcNAcylation. Biochem J 420, 221-227.
Borodkin VS, van Aalten DM (2010) An efficient and versatile synthesis of GlcNAcstatins-potent
and selective O-GlcNAcase inhibitors built on the
tetrahydroimidazo[1,2-a]pyridine scaffold. Tetrahedron
66, 7838-7849.
Kim C, Nam DW, Park SY, Song H, Hong HS,
Boo JH, Jung ES, Kim Y, Baek JY, Kim KS,
Cho JW, Mook-Jung I (2012) O-linked beta-Nacetylglucosaminidase inhibitor attenuates beta-amyloid
plaque and rescues memory impairment. Neurobiol Aging,
doi:10.1016/j.neurobiolaging.2012.03.001 [Epubl ahead
of print].
[5] Kim C, Nam DW, Park SY, Song H, Hong
HS, Boo JH, Jung ES, Kim Y, Baek JY, Kim
KS, Cho JW, Mook-Jung I (2012) O-linked beta-Nacetylglucosaminidase inhibitor attenuates beta-amyloid
plaque and rescues memory impairment. Neurobiol Aging,
doi:10.1016/j.neurobiolaging.2012.03.001
[6] Macauley MS, Whitworth GE, Debowski AW, Chin D,
Vocadlo DJ (2005) O-GlcNAcase uses substrate-assisted
catalysis: kinetic analysis and development of highly selective mechanism-inspired inhibitors. J Biol Chem 280,
25313-25322.
Yuzwa SA, Macauley MS, Heinonen JE, Shan X,
Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ, Vocadlo DJ (2008) A potent
mechanism-inspired O-GlcNAcase inhibitor that blocks
phosphorylation of tau in vivo. Nat Chem Biol 4, 483490.
Yuzwa SA, Vocadlo DJ (2009) O-GlcNAc modification
and the tauopathies: Insights from chemical biology. Curr
Alzheimer Res 6, 451-454.
Yuzwa SA, Yadav AK, Skorobogatko Y, Clark T, Vosseller
K, Vocadlo DJ (2011) Mapping O-GlcNAc modification
652
[1512]
[1513]
[1514]
[1515]
[1516]
[1517]
[1518]
[1519]
[1520]
[1521]
[1522]
[1523]
[1524]
[1525]
[1526]
[1527]
[1528]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
sites on tau and generation of a site-specific O-GlcNAc tau
antibody. Amino Acids 40, 857-868.
Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko
Y, Vosseller K, Vocadlo DJ (2012) Increasing O-GlcNAc
slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol 8, 393-399.
Fischer PM (2008) Turning down tau phosphorylation. Nat
Chem Biol 4, 448-449.
Lefebvre T (2012) Recall sugars, forget Alzheimer’s.
Nature Chem Biol 8, 325-326.
Yu Y, Zhang L, Li X, Run X, Liang Z, Li Y, Liu
Y, Lee MH, Grundke-Iqbal I, Iqbal K, Vocadlo DJ,
Liu F, Gong CX (2012) Differential effects of an OGlcNAcase inhibitor on tau phosphorylation. PLoS One 7,
e35277.
Mouri A, Noda Y, Shimizu S, Tsujimoto Y, Nabeshima T
(2010) The role of cyclophilin D in learning and memory.
Hippocampus 20, 293-304.
Muirhead KE, Borger E, Aitken L, Conway SJ, GunnMoore FJ (2010) The consequences of mitochondrial
amyloid beta-peptide in Alzheimer’s disease. Biochem J
426, 255-270.
Koren J III, Jinwal UK, Davey Z, Kiray J, Arulselvam K,
Dickey CA (2011) Bending tau into shape: The emerging role of peptidyl-prolyl isomerases in tauopathies. Mol
Neurobiol 44, 65-70.
Golde TE (2006) Disease modifying therapy for AD?
J Neurochem 99, 689-707.
Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase
inhibitors: A promising target for cognition enhancement.
Psychopharmacology (Berl) 202, 419-443.
Rutten K, Van Donkelaar EL, Ferrington L, Blokland
A, Bollen E, Steinbusch HW, Kelly PA, Prickaerts JH
(2009) Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose
utilization in rats. Neuropsychopharmacology 34, 19141925.
Schmidt CJ (2010) Phosphodiesterase inhibitors as potential cognition enhancing agents. Curr Top Med Chem 10,
222-230.
Blokland A, Menniti FS, Prickaerts J (2012) PDE inhibition and cognition enhancement. Expert Opin Ther Pat 22,
349-354.
Xu Y, Zhang HT, O’Donnell JM (2011) Phosphodiesterases in the central nervous system: Implications in
mood and cognitive disorders. Handb Exp Pharmacol 447485.
Sierksma AS, Rutten K, Sydlik S, Rostamian S, Steinbusch HW, van den Hove DL, Prickaerts J (2013) Chronic
phosphodiesterase type 2 inhibition improves memory in
the APPswe/PS1dE9 mouse model of Alzheimer’s disease.
Neuropharmacology 61, 124-136.
Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL,
Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen
T, Kiselyov AS, Stewart LJ, Gurney ME (2010) Design of
phosphodiesterase 4D (PDE4D) allosteric modulators for
enhancing cognition with improved safety. Nat Biotechnol
28, 63-70.
Ghavami A, Hirst WD, Novak TJ (2006) Selective phosphodiesterase (PDE)-4 inhibitors: A novel approach to
treating memory deficit? Drugs R D 7, 63-71.
Prickaerts J, Sik A, van Staveren WC, Koopmans G, Steinbusch HW, van der Staay FJ, de Vente J, Blokland A (2004)
Phosphodiesterase type 5 inhibition improves early mem-
[1529]
[1530]
[1531]
[1532]
[1533]
[1534]
[1535]
[1536]
[1537]
[1538]
[1539]
[1540]
[1541]
ory consolidation of object information. Neurochem Int 45,
915-928.
Reneerkens OA, Rutten K, Akkerman S, Blokland A, Shaffer CL, Menniti FS, Steinbusch HW, Prickaerts J (2012)
Phosphodiesterase type 5 (PDE5) inhibition improves
object recognition memory: Indications for central and
peripheral mechanisms. Neurobiol Learn Mem 97, 370379.
Chappie T, Humphrey J, Menniti F, Schmidt C (2009)
PDE10A inhibitors: An assessment of the current CNS
drug discovery landscape. Curr Opin Drug Discov Devel
12, 458-467.
Grauer SM, Pulito VL, Navarra RL, Kelly MP, Kelley C,
Graf R, Langen B, Logue S, Brennan J, Jiang L, Charych
E, Egerland U, Liu F, Marquis KL, Malamas M, Hage
T, Comery TA, Brandon NJ (2009) Phosphodiesterase
10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia.
J Pharmacol Exp Ther 331, 574-590.
Williams M, Risley EA (1979) Enhancement of the binding of 3H-diazepam to rat brain membranes in vitro by
SQ 20009, A novel anxiolytic, gamma-aminobutyric acid
(GABA) and muscimol. Life Sci 24, 833-841.
Supavilai P, Karobath M (1980) Interaction of SQ 20009
and GABA-like drugs as modulators of benzodiazepine
receptor binding. Eur J Pharmacol 62, 229-233.
Ticku MK, Davis WC (1982) Molecular interactions of
etazolate with benzodiazepine and picrotoxinin binding
sites. J Neurochem 38, 1180-1182.
Barnes DM, White WF, Dichter MA (1983) Etazolate (SQ20009): Electrophysiology and effects on
[3H]flunitrazepam binding in cultured cortical neurons. J
Neurosci 3, 762-772.
Borea PA, Supavilai P, Karobath M (1983) Differential
modulation of etazolate or pentobarbital enhanced [3H]
muscimol binding by benzodiazepine agonists and inverse
agonists. Brain Res 280, 383-386.
Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms
JF, Hou X, Marr ES, Menniti FS, Nelson F, O’Connor R,
Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ,
Suiciak JA, Liras S (2009) Discovery of a novel class
of phosphodiesterase 10A inhibitors and identification
of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1Hpyrazol-3-yl)-phenoxymethyl]- quinoline (PF-2545920)
for the treatment of schizophrenia. J Med Chem 52, 51885196.
Torremans A, Ahnaou A, Van HA, Straetemans R, Geys H,
Vanhoof G, Meert TF, Drinkenburg WH (2010) Effects of
phosphodiesterase 10 inhibition on striatal cyclic AMP and
peripheral physiology in rats. Acta Neurobiol Exp (Wars )
70, 13-19.
Dedeurwaerdere S, Wintmolders C, Vanhoof G, Langlois
X (2011) Patterns of brain glucose metabolism induced
by phosphodiesterase 10A inhibitors in the mouse: A
potential translational biomarker. J Pharmacol Exp Ther
339, 210-217.
Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau
HJ, Grunwald C, Fan KY, Parris K, Langen B, Egerland U,
Hage T, Marquis KL, Grauer S, Brennan J, Navarra R, Graf
R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN,
Hoefgen N, Brandon NJ (2011) Highly potent, selective,
and orally active phosphodiesterase 10A inhibitors. J Med
Chem 54, 7621-7638.
Hu E, Ma J, Biorn C, Lester-Zeiner D, Cho R, Rumfelt S,
Kunz RK, Nixey T, Michelsen K, Miller S, Shi J, Wong
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1542]
[1543]
[1544]
[1545]
[1546]
[1547]
[1548]
[1549]
[1550]
[1551]
[1552]
J, Hill Della PG, Able J, Talreja S, Hwang DR, Hitchcock SA, Porter A, Immke D, Allen JR, Treanor J, Chen
H (2012) Rapid identification of a novel small molecule
phosphodiesterase 10A (PDE10A) tracer. J Med Chem 55,
4776-4787.
Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C,
Andrews KL, Zhang J, Chmait S, Kogan J, Lindstrom M,
Hitchcock SA, Treanor J (2012) Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines
as novel phosphodiesterase 10A (PDE10A) inhibitors.
Bioorg Med Chem Lett 22, 2262-2265.
Lee HR, Park SY, Kim HY, Shin HK, Lee WS, Rhim
BY, Hong KW, Kim CD (2012) Protection by cilostazol
against amyloid-beta(1-40)-induced suppression of viability and neurite elongation through activation of CK2alpha
in HT22 mouse hippocampal cells. J Neurosci Res 90,
1566-1576.
Bruno O, Fedele E, Prickaerts J, Parker LA, Canepa E,
Brullo C, Cavallero A, Gardella E, Balbi A, Domenicotti
C, Bollen E, Gijselaers HJ, Vanmierlo T, Erb K, Limebeer
CL, Argellati F, Marinari UM, Pronzato MA, Ricciarelli R
(2011) GEBR-7b, a novel PDE4D selective inhibitor that
improves memory in rodents at non-emetic doses. Br J
Pharmacol 164, 2054-2063.
Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E,
Perez-Roldan JM, Garcia-Barroso C, Franco R, Aguirre N,
Garcia-Osta A (2011) Sildenafil restores cognitive function without affecting beta-amyloid burden in a mouse
model of Alzheimer’s disease. Br J Pharmacol 164, 20292041.
Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M, Unceta N, Rico AJ, Goicolea MA, Salles J, Lanciego JL,
Oyarzabal J, Franco R, Cuadrado-Tejedor M, Garcia-Osta
A (2013) Tadalafil crosses the blood-brain barrier and
reverses cognitive dysfunction in a mouse model of AD.
Neuropharmacology 61, 114-123.
Smith SM, Uslaner JM, Cox CD, Huszar SL, Cannon
CE, Vardigan JD, Eddins D, Toolan DM, Kandebo M,
Yao L, Raheem IT, Schreier JD, Breslin MJ, Coleman
PJ, Renger JJ (2013) The novel phosphodiesterase 10A
inhibitor THPP-1 has antipsychotic-like effects in rat and
improves cognition in rat and rhesus monkey. Neuropharmacology 61, 215-223.
Treves TA, Korczyn AD (1999) Denbufylline in dementia:
A double-blind controlled study. Dement Geriatr Cogn
Disord 10, 505-510.
MacDonald E, Van der LH, Pocock D, Cole C, Thomas
N, VandenBerg PM, Bourtchouladze R, Kleim JA (2007)
A novel phosphodiesterase type 4 inhibitor, HT-0712,
enhances rehabilitation-dependent motor recovery and
cortical reorganization after focal cortical ischemia.
Neurorehabil Neural Repair 21, 486-496.
Giembycz MA (2008) Can the anti-inflammatory potential of PDE4 inhibitors be realized: Guarded optimism or
wishful thinking? Br J Pharmacol 155, 288-290.
Gallant M, Aspiotis R, Day S, Dias R, Dube D, Dube
L, Friesen RW, Girard M, Guay D, Hamel P, Huang Z,
Lacombe P, Laliberte S, Levesque JF, Liu S, MacDonald D,
Mancini J, Nicholson DW, Styhler A, Townson K, Waters
K, Young RN, Girard Y (2010) Discovery of MK-0952,
a selective PDE4 inhibitor for the treatment of long-term
memory loss and mild cognitive impairment. Bioorg Med
Chem Lett 20, 6387-6393.
Hersperger R, Bray-French K, Mazzoni L, Muller T (2000)
Palladium-catalyzed cross-coupling reactions for the syn-
[1553]
[1554]
[1555]
[1556]
[1557]
[1558]
[1559]
[1560]
[1561]
[1562]
[1563]
653
thesis of 6, 8-disubstituted 1,7-naphthyridines: A novel
class of potent and selective phosphodiesterase type 4D
inhibitors. J Med Chem 43, 675-682.
Hersperger R, Dawson J, Mueller T (2002) Synthesis
of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6yl)-benzoic acid: A potent and selective phosphodiesterase
type 4D inhibitor. Bioorg Med Chem Lett 12, 233-235.
Trifilieff A, Wyss D, Walker C, Mazzoni L, Hersperger
R (2002) Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1,2,5]oxadiazol-5yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171),
a 1,7-naphthyridine derivative, with anti-inflammatory
activities. J Pharmacol Exp Ther 301, 241-248.
Hutson PH, Finger EN, Magliaro BC, Smith SM,
Converso A, Sanderson PE, Mullins D, Hyde LA,
Eschle BK, Turnbull Z, Sloan H, Guzzi M, Zhang
X, Wang A, Rindgen D, Mazzola R, Vivian JA, Eddins
D, Uslaner JM, Bednar R, Gambone C, Le-Mair W,
Marino MJ, Sachs N, Xu G, Parmentier-Batteur S (2011)
The selective phosphodiesterase 9 (PDE9) inhibitor PF04447943(6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)
pyrrolidin-3-yl]-1-(tetrahydro-2H-py ran-4-yl)- 1,5dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances
synaptic plasticity and cognitive function in rodents.
Neuropharmacology 61, 665-676.
Verhoest PR, Fonseca KR, Hou X, Proulx-Lafrance
C, Corman M, Helal CJ, Claffey MM, Tuttle JB,
Coffman KJ, Liu S, Nelson F, Kleiman RJ, Menniti FS,
Schmidt CJ, Vanase-Frawley M, Liras S (2012) Design
and discovery of 6-[(3S,4S)-4-Methyl-1-(pyrimidin-2ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyr an-4-yl)
-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF04447943), a selective brain penetrant PDE9A inhibitor
for the treatment of cognitive disorders. J Med Chem, doi:
10.1021/jm3007799 [Epubl ahead of print].
Plaschke K, Martin E, Bardenheuer HJ (1998) Effect of
propentofylline on hippocampal brain energy state and
amyloid precursor protein concentration in a rat model
of cerebral hypoperfusion. J Neural Transm 105, 10651077.
Yamada K, Tanaka T, Senzaki K, Kameyama T, Nabeshima
T (1998) Propentofylline improves learning and memory
deficits in rats induced by beta-amyloid protein-(1-40). Eur
J Pharmacol 349, 15-22.
Rutten K, Prickaerts J, Blokland A (2006) Rolipram
reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms
of action. Neurobiol Learn Mem 85, 132-138.
Rutten K, Prickaerts J, Schaenzle G, Rosenbrock H, Blokland A (2008) Sub-chronic rolipram treatment leads to
a persistent improvement in long-term object memory in
rats. Neurobiol Learn Mem 90, 569-575.
Rutten K, Basile JL, Prickaerts J, Blokland A, Vivian JA
(2008) Selective PDE inhibitors rolipram and sildenafil
improve object retrieval performance in adult cynomolgus
macaques. Psychopharmacology (Berl) 196, 643-648.
Rutten K, Wallace TL, Works M, Prickaerts. J, Blokland
A, Novak TJ, Santarelli L, Misner DL (2011) Enhanced
long-term depression and impaired reversal learning in
phosphodiesterase 4B-knockout (PDE4B(−/−)) mice.
Neuropharmacology 61, 138-147.
de Lima MN, Presti-Torres J, Garcia VA, Guimaraes MR,
Scalco FS, Roesler R, Schroder N (2008) Amelioration
of recognition memory impairment associated with iron
loading or aging by the type 4-specific phosphodiesterase
654
[1564]
[1565]
[1566]
[1567]
[1568]
[1569]
[1570]
[1571]
[1572]
[1573]
[1574]
[1574]
[1575]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
inhibitor rolipram in rats. Neuropharmacology 55, 788792.
Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T,
Kelly MP (2007) Rolipram: A specific phosphodiesterase
4 inhibitor with potential antipsychotic activity. Neuroscience 144, 239-246.
Roesler R, Schroder N (2011) Cognitive enhancers: Focus
on modulatory signaling influencing memory consolidation. Pharmacol Biochem Behav 99, 155-163.
Wang C, Yang XM, Zhuo YY, Zhou H, Lin HB, Cheng
YF, Xu JP, Zhang HT (2012) The phosphodiesterase4 inhibitor rolipram reverses Abeta-induced cognitive impairment and neuroinflammatory and apoptotic
responses in rats. Int J Neuropsychopharmacol 15, 749766.
Sanchez-Mejia RO, Newman JW, Toh S, Yu GQ, Zhou Y,
Halabisky B, Cisse M, Scearce-Levie K, Cheng IH, Gan L,
Palop JJ, Bonventre JV, Mucke L (2008) Phospholipase A2
reduction ameliorates cognitive deficits in a mouse model
of Alzheimer’s disease. Nat Neurosci 11, 1311-1318.
Sanchez-Mejia RO, Mucke L (2010) Phospholipase A2
and arachidonic acid in Alzheimer’s disease. Biochim Biophys Acta 1801, 784-790.
Gentile MT, Reccia MG, Sorrentino PP, Vitale E, Sorrentino G, Puca AA, Colucci-D’Amato L (2012) Role
of cytosolic calcium-dependent phospholipase A2 in
Alzheimer’s disease pathogenesis. Mol Neurobiol 45, 596604.
Mancuso DJ, Kotzbauer P, Wozniak DF, Sims HF, Jenkins
CM, Guan S, Han X, Yang K, Sun G, Malik I, Conyers S, Green KG, Schmidt RE, Gross RW (2009) Genetic
ablation of calcium-independent phospholipase A2gamma
leads to alterations in hippocampal cardiolipin content and
molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem
284, 35632-35644.
Oliveira TG, Chan RB, Tian H, Laredo M, Shui G,
Staniszewski A, Zhang H, Wang L, Kim TW, Duff KE,
Wenk MR, Arancio O, Di PG (2010) Phospholipase d2
ablation ameliorates Alzheimer’s disease-linked synaptic
dysfunction and cognitive deficits. J Neurosci 30, 1641916428.
Oliveira TG, Di Pado G (2010) Phospholipase D in brain
function and Alzheimer’s disease. Biochim Biophys Acta
1801, 799-805.
Cesari M, Pahor M, Incalzi RA (2010) Plasminogen
activator inhibitor-1 (PAI-1): A key factor linking fibrinolysis and age-related subclinical and clinical conditions.
Cardiovasc Ther 28, e72-e91.
Weng SC, Shu KH, Tang YJ, Sheu WH, Tarng DC, Wu
MJ, Chen YM, Chuang YW (2012) Progression of cognitive dysfunction in elderly chronic kidney disease patients
in a veteran’s institution in central Taiwan: A 3-year longitudinal study. Intern Med 51, 29-35.
[7]Cho H, Joo Y, Kim S, Woo RS, Lee SH, Kim HS (2012)
Plasminogen activator inhibitor-1 promotes synaptogenesis and protects against Abeta(1-42)-induced neurotoxicity
in primary cultured hippocampal neurons. Int J Neurosci,
doi:10.3109/00207454.2012.724127Miralbell J, Soriano JJ, Spulber G, Lopez-Cancio E, Arenillas JF, Bargallo N, Galan A, Barrios MT, Caceres C,
Alzamora MT, Pera G, Kivipelto M, Wahlund LO, Davalos A, Mataro M (2012) Structural brain changes and
cognition in relation to markers of vascular dysfunction.
Neurobiol Aging 33, 1003-1017.
[1576]
[1577]
[1578]
[1579]
[1580]
[1581]
[1582]
[1583]
[1584]
[1585]
[1586]
[1587]
[1588]
[1589]
[1590]
Quinn TJ, Gallacher J, Deary IJ, Lowe GD, Fenton C,
Stott DJ (2011) Association between circulating hemostatic measures and dementia or cognitive impairment:
Systematic review and meta-analyzes. J Thromb Haemost
9, 1475-1482.
Martorana A, Sancesario GM, Esposito Z, Nuccetelli M,
Sorge R, Formosa A, Dinallo V, Bernardi G, Bernardini
S, Sancesario G (2012) Plasmin system of Alzheimer’s
disease patients: CSF analysis. J Neural Transm 119, 763769.
Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori
Y, Gum E, Liu J, Swanson RA (2003) Hypoglycemic
neuronal death and cognitive impairment are prevented
by poly(ADP-ribose) polymerase inhibitors administered
after hypoglycemia. J Neurosci 23, 10681-10690.
Suh SW, Aoyama K, Matsumori Y, Liu J, Swanson RA
(2005) Pyruvate administered after severe hypoglycemia
reduces neuronal death and cognitive impairment. Diabetes 54, 1452-1458.
Whalen MJ, Clark RS, Dixon CE, Robichaud P, Marion
DW, Vagni V, Graham SH, Virag L, Hasko G, Stachlewitz
R, Szabo C, Kochanek PM (1999) Reduction of cognitive and motor deficits after traumatic brain injury in mice
deficient in poly(ADP-ribose) polymerase. J Cereb Blood
Flow Metab 19, 835-842.
Russo AL, Kwon HC, Burgan WE, Carter D, Beam K,
Weizheng X, Zhang J, Slusher BS, Chakravarti A, Tofilon
PJ, Camphausen K (2009) In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose)
polymerase inhibitor E7016. Clin Cancer Res 15, 607-612.
Rossner S, Schulz I, Zeitschel U, Schliebs R, Bigl V,
Demuth HU (2005) Brain prolyl endopeptidase expression
in aging, APP transgenic mice and Alzheimer’s disease.
Neurochem Res 30, 695-702.
Mannisto PT, Venalainen J, Jalkanen A, Garcia-Horsman
JA (2007) Prolyl oligopeptidase: A potential target for the
treatment of cognitive disorders. Drug News Perspect 20,
293-305.
Garcia-Horsman JA (2011) Prolyl oligopeptidase in brain
function and dysfunction. CNS Neurol Disord Drug Target
10, 296.
Lopez A, Tarrago T, Giralt E (2011) Low molecular weight
inhibitors of prolyl oligopeptidase: A review of compounds patented from 2003 to 2010. Expert Opin Ther
Pat 21, 1023-1044.
Jalkanen AJ, Hakkarainen JJ, Lehtonen M, Venalainen
T, Kaariainen TM, Jarho E, Suhonen M, Forsberg MM
(2011) Brain pharmacokinetics of two prolyl oligopeptidase inhibitors, JTP-4819 and KYP-2047, in the rat. Basic
Clin Pharmacol Toxicol 109, 443-451.
Jalkanen AJ, Savolainen K, Forsberg MM (2011) Inhibition of prolyl oligopeptidase by KYP-2047 fails to increase
the extracellular neurotensin and substance P levels in rat
striatum. Neurosci Lett 502, 107-111.
Jalkanen AJ, Piepponen TP, Hakkarainen JJ, De Meester
I, Lambeir AM, Forsberg MM (2012) The effect of prolyl oligopeptidase inhibition on extracellular acetylcholine
and dopamine levels in the rat striatum. Neurochem Int 60,
301-309.
Park DH, Park SJ, Kim JM, Jung WY, Ryu JH (2010)
Subchronic administration of rosmarinic acid, a natural
prolyl oligopeptidase inhibitor, enhances cognitive performances. Fitoterapia 81, 644-648.
Kamei H, Ueki T, Obi Y, Fukagawa Y, Oki T (1992)
Protective effect of eurystatins A and B, new prolyl
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1591]
[1592]
[1593]
[1594]
[1595]
[1596]
[1597]
[1598]
[1599]
[1600]
[1601]
[1602]
[1603]
[1604]
endopeptidase inhibitors, on scopolamine-induced amnesia in rats. Jpn J Pharmacol 60, 377-380.
Toda S, Obi Y, Numata K, Hamagishi Y, Tomita K,
Komiyama N, Kotake C, Furumai T, Oki T (1992) Eurystatins A and B, new prolyl endopeptidase inhibitors. I.
Taxonomy, production, isolation and biological activities.
J Antibiot (Tokyo) 45, 1573-1579.
Toda S, Kotake C, Tsuno T, Narita Y, Yamasaki T, Konishi
M (1992) Eurystatins A and B, new prolyl endopeptidase
inhibitors. II. Physico-chemical properties and structure
determination. J Antibiot (Tokyo) 45, 1580-1586.
Suzuki K, Toda S, Furumai T, Fukagawa Y, Oki T (1994)
Eurystatins A and B, new prolyl endopeptidase inhibitors.
III. Fermentation and controlled biosynthesis of eurystatin
analogs by Streptomyces eurythermus. J Antibiot (Tokyo)
47, 982-991.
Toide K, Iwamoto Y, Fujiwara T, Abe H (1995) JTP-4819:
A novel prolyl endopeptidase inhibitor with potential as
a cognitive enhancer. J Pharmacol Exp Ther 274, 13701378.
Toide K, Shinoda M, Iwamoto Y, Fujiwara T, Okamiya K,
Uemura A (1997) A novel prolyl endopeptidase inhibitor,
JTP-4819, with potential for treating Alzheimer’s disease.
Behav Brain Res 83, 147-151.
Toide K, Shinoda M, Fujiwara T, Iwamoto Y (1997) Effect
of a novel prolyl endopeptidase inhibitor, JTP-4819, on
spatial memory and central cholinergic neurons in aged
rats. Pharmacol Biochem Behav 56, 427-434.
Toide K, Shinoda M, Miyazaki A (1998) A novel prolyl endopeptidase inhibitor, JTP-4819–its behavioral and
neurochemical properties for the treatment of Alzheimer’s
disease. Rev Neurosci 9, 17-29.
Wallen EA, Christiaans JA, Jarho EM, Forsberg MM,
Venalainen JI, Mannisto PT, Gynther J (2003) New prolyl oligopeptidase inhibitors developed from dicarboxylic
acid bis(l-prolyl-pyrrolidine) amides. J Med Chem 46,
4543-4551.
Katsube N, Sunaga K, Chuang DM, Ishitani R (1996)
ONO-1603, a potential antidementia drug, shows neuroprotective effects and increases m3-muscarinic receptor
mRNA levels in differentiating rat cerebellar granule neurons. Neurosci Lett 214, 151-154.
Katsube N, Sunaga K, Aishita H, Chuang DM, Ishitani R
(1999) ONO-1603, a potential antidementia drug, delays
age-induced apoptosis and suppresses overexpression of
glyceraldehyde-3-phosphate dehydrogenase in cultured
central nervous system neurons. J Pharmacol Exp Ther
288, 6-13.
Barelli H, Petit A, Hirsch E, Wilk S, De Nanteuil G, Morain
P, Checler F (1999) S 17092-1, a highly potent, specific and
cell permeant inhibitor of human proline endopeptidase.
Biochem Biophys Res Commun 257, 657-661.
Morain P, Robin JL, De Nanteuil G, Jochemsen R, Heidet
V, Guez D (2000) Pharmacodynamic and pharmacokinetic
profile of S 17092, a new orally active prolyl endopeptidase
inhibitor, in elderly healthy volunteers. A phase I study. Br
J Clin Pharmacol 50, 350-359.
Morain P, Lestage P, De Nanteuil G, Jochemsen R, Robin
JL, Guez D, Boyer PA (2002) S 17092: A prolyl endopeptidase inhibitor as a potential therapeutic drug for memory
impairment. Preclinical and clinical studies. CNS Drug Rev
8, 31-52.
Morain P, Boeijinga PH, Demazieres A, De Nanteuil G,
Luthringer R (2007) Psychotropic profile of S 17092, a
prolyl endopeptidase inhibitor, using quantitative EEG in
[1605]
[1606]
[1607]
[1608]
[1609]
[1610]
[1611]
[1612]
[1613]
[1614]
[1615]
[1616]
[1617]
[1618]
655
young healthy volunteers. Neuropsychobiology 55, 176183.
Bellemere G, Morain P, Vaudry H, Jegou S (2003) Effect
of S 17092, a novel prolyl endopeptidase inhibitor, on
substance P and alpha-melanocyte-stimulating hormone
breakdown in the rat brain. J Neurochem 84, 919-929.
Petit A, Barelli H, Morain P, Checler F (2000) Novel proline endopeptidase inhibitors do not modify Abeta40/42
formation and degradation by human cells expressing
wild-type and swedish mutated beta-amyloid precursor
protein. Br J Pharmacol 130, 1613-1617.
Arai H, Nishioka H, Niwa S, Yamanaka T, Tanaka Y,
Yoshinaga K, Kobayashi N, Miura N, Ikeda Y (1993) Synthesis of prolyl endopeptidase inhibitors and evaluation of
their structure-activity relationships: In vitro inhibition of
prolyl endopeptidase from canine brain. Chem Pharm Bull
(Tokyo) 41, 1583-1588.
Tanaka Y, Niwa S, Nishioka H, Yamanaka T, Torizuka
M, Yoshinaga K, Kobayashi N, Ikeda Y, Arai H (1994)
New potent prolyl endopeptidase inhibitors: Synthesis and
structure-activity relationships of indan and tetralin derivatives and their analogues. J Med Chem 37, 2071-2078.
Portevin B, Benoist A, Remond G, Herve Y, Vincent
M, Lepagnol J, De Nanteuil G (1996) New prolyl
endopeptidase inhibitors: In vitro and in vivo activities of azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane,
and perhydroindole derivatives. J Med Chem 39, 23792391.
Jarho EM, Venalainen JI, Poutiainen S, Leskinen H,
Vepsalainen J, Christiaans JA, Forsberg MM, Mannisto
PT, Wallen EA (2007) 2(S)-(Cycloalk-1-enecarbonyl)1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4phenylbutanoyl)pyrrolidines as prolyl oligopeptidase
inhibitors. Bioorg Med Chem 15, 2024-2031.
Nakajima T, Ono Y, Kato A, Maeda J, Ohe T (1992) Y29794–a non-peptide prolyl endopeptidase inhibitor that
can penetrate into the brain. Neurosci Lett 141, 156-160.
Kato A, Fukunari A, Sakai Y, Nakajima T (1997)
Prevention of amyloid-like deposition by a selective
prolyl endopeptidase inhibitor, Y-29794, in senescenceaccelerated mouse. J Pharmacol Exp Ther 283, 328-335.
Miura N, Shibata S, Watanabe S (1995) Increase in the septal vasopressin content by prolyl endopeptidase inhibitors
in rats. Neurosci Lett 196, 128-130.
Miura N, Shibata S, Watanabe S (1997) Z-321, a prolyl endopeptidase inhibitor, augments the potentiation of
synaptic transmission in rat hippocampal slices. Behav
Brain Res 83, 213-216.
Umemura K, Kondo K, Ikeda Y, Nishimoto M, Hiraga
Y, Yoshida Y, Nakashima M (1999) Pharmacokinetics
and safety of Z-321, a novel specific orally active prolyl endopeptidase inhibitor, in healthy male volunteers.
J Clin Pharmacol 39, 462-470.
Shishido Y, Furushiro M, Tanabe S, Taniguchi A,
Hashimoto S, Yokokura T, Shibata S, Yamamoto T, Watanabe S (1998) Effect of ZTTA, a prolyl endopeptidase
inhibitor, on memory impairment in a passive avoidance
test of rats with basal forebrain lesions. Pharm Res 15,
1907-1910.
Urade Y, Hayaishi O (2000) Biochemical, structural,
genetic, physiological, and pathophysiological features of
lipocalin-type prostaglandin D synthase. Biochim Biophys
Acta 1482, 259-271.
Urade Y, Hayaishi O (2000) Prostaglandin D synthase:
Structure and function. Vitam Horm 58, 89-120.
656
[1619]
[1620]
[1621]
[1622]
[1623]
[1624]
[1625]
[1626]
[1627]
[1628]
[1629]
[1630]
[1631]
[1632]
[1633]
[1634]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Hara S, Kamei D, Sasaki Y, Tanemoto A, Nakatani Y,
Murakami M (2010) Prostaglandin E synthases: Understanding their pathophysiological roles through mouse
genetic models. Biochimie 92, 651-659.
Iyer JP, Srivastava PK, Dev R, Dastidar SG, Ray A (2009)
Prostaglandin E(2) synthase inhibition as a therapeutic
target. Expert Opin Ther Targets 13, 849-865.
Matousek SB, Hein AM, Shaftel SS, Olschowka JA,
Kyrkanides S, O’Banion MK (2010) Cyclooxygenase1 mediates prostaglandin E(2) elevation and contextual
memory impairment in a model of sustained hippocampal
interleukin-1beta expression. J Neurochem 114, 247-258.
Kuroki Y, Sasaki Y, Kamei D, Akitake Y, Takahashi M,
Uematsu S, Akira S, Nakatani Y, Kudo I, Hara S (2012)
Deletion of microsomal prostaglandin E synthase-1 protects neuronal cells from cytotoxic effects of beta-amyloid
peptide fragment 31-35. Biochem Biophys Res Commun
424, 409-413.
Hongpaisan J, Alkon DL (2007) A structural basis for
enhancement of long-term associative memory in single
dendritic spines regulated by PKC. Proc Natl Acad Sci U
S A 104, 19571-19576.
Hongpaisan J, Sun MK, Alkon DL (2011) PKC epsilon
activation prevents synaptic loss, Abeta elevation, and
cognitive deficits in Alzheimer’s disease transgenic mice.
J Neurosci 31, 630-643.
Sun MK, Alkon DL (2006) Protein kinase C pharmacology: Perspectives on therapeutic potentials as antidementic
and cognitive agents. Recent Pat CNS Drug Discov 1, 147156.
Sun MK, Alkon DL (2010) Pharmacology of protein
kinase C activators: Cognition-enhancing and antidementic therapeutics. Pharmacol Ther 127, 66-77.
Sun MK, Alkon DL (2009) Protein kinase C activators
as synaptogenic and memory therapeutics. Arch Pharm
(Weinheim) 342, 689-698.
Sun MK, Alkon DL (2005) Protein kinase C isozymes:
Memory therapeutic potential. Curr Drug Targets CNS
Neurol Disord 4, 541-552.
Govoni S, Amadio M, Battaini F, Pascale A (2010) Senescence of the brain: Focus on cognitive kinases. Curr Pharm
Des 16, 660-671.
Kozikowski AP, Nowak I, Petukhov PA, Etcheberrigaray
R, Mohamed A, Tan M, Lewin N, Hennings H, Pearce LL,
Blumberg PM (2003) New amide-bearing benzolactambased protein kinase C modulators induce enhanced
secretion of the amyloid precursor protein metabolite sAPPalpha. J Med Chem 46, 364-373.
Lee J, Kang JH, Han KC, Kim Y, Kim SY, Youn HS, MookJung I, Kim H, Lo Han JH, Ha HJ, Kim YH, Marquez VE,
Lewin NE, Pearce LV, Lundberg DJ, Blumberg PM (2006)
Branched diacylglycerol-lactones as potent protein kinase
C ligands and alpha-secretase activators. J Med Chem 49,
2028-2036.
Mach UR, Lewin NE, Blumberg PM, Kozikowski AP
(2006) Synthesis and pharmacological evaluation of 8- and
9-substituted benzolactam-v8 derivatives as potent ligands
for protein kinase C, a therapeutic target for Alzheimer’s
disease. ChemMedChem 1, 307-314.
Sun MK, Alkon DL (2005) Dual effects of bryostatin-1
on spatial memory and depression. Eur J Pharmacol 512,
43-51.
Sun MK, Alkon DL (2009) Protein kinase C activators
as synaptogenic and memory therapeutics. Arch Pharm
(Weinheim) 342, 689-698.
[1635]
[1636]
[1637]
[1638]
[1639]
[1640]
[1641]
[1642]
[1643]
[1644]
[1645]
[1646]
[1647]
[1648]
Sun MK, Alkon DL (2010) Pharmacology of protein
kinase C activators: Cognition-enhancing and antidementic therapeutics. Pharmacol Ther 127, 66-77.
Sun MK, Hongpaisan J, Nelson TJ, Alkon DL (2008) Poststroke neuronal rescue and synaptogenesis mediated in
vivo by protein kinase C in adult brains. Proc Natl Acad
Sci U S A 105, 13620-13625.
Sun MK, Hongpaisan J, Alkon DL (2009) Postischemic
PKC activation rescues retrograde and anterograde longterm memory. Proc Natl Acad Sci U S A 106, 14676-14680.
Tanaka A, Nishizaki T (2003) The newly synthesized
linoleic acid derivative FR236924 induces a long-lasting
facilitation of hippocampal neurotransmission by targeting nicotinic acetylcholine receptors. Bioorg Med Chem
Lett 13, 1037-1040.
Kanno T, Yaguchi T, Yamamoto S, Yamamoto H, Fujikawa
H, Nagata T, Tanaka A, Nishizaki T (2005) 8-[2(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid
stimulates GABA release from interneurons projecting to
CA1 pyramidal neurons in the rat hippocampus via presynaptic alpha7 acetylcholine receptors. J Neurochem 95,
695-702.
Kanno T, Yamamoto H, Yaguchi T, Hi R, Mukasa T,
Fujikawa H, Nagata T, Yamamoto S, Tanaka A, Nishizaki
T (2006) The linoleic acid derivative DCP-LA selectively
activates PKC-epsilon, possibly binding to the phosphatidylserine binding site. J Lipid Res 47, 1146-1156.
Yaguchi T, Nagata T, Mukasa T, Fujikawa H, Yamamoto H,
Yamamoto S, Iso H, Tanaka A, Nishizaki T (2006) Linoleic
acid derivative DCP-LA improves learning impairment in
SAMP8. Neuroreport 17, 105-108.
Fitzpatrick CJ, Lombroso PJ (2011) The Role of
Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in
Cognition. Front Neuroanat 5, 47.
Pelov I, Teltsh O, Greenbaum L, Rigbi A, Kanyas-Sarner
K, Lerer B, Lombroso P, Kohn Y (2012) Involvement
of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition.
Psychiatr Genet 22, 168-176.
Leblanc M, Kulle B, Sundet K, Agartz I, Melle I, Djurovic
S, Frigessi A, Andreassen OA (2012) Genome-wide study
identifies PTPRO and WDR72 and FOXQ1-SUMO1P1
interaction associated with neurocognitive function. J Psychiatr Res 46, 271-278.
Patrignani C, Magnone MC, Tavano P, Ardizzone M,
Muzio V, Greco B, Zaratin PF (2008) Knockout mice
reveal a role for protein tyrosine phosphatase H1 in cognition. Behav Brain Funct 4, 36.
Raz L, Zhang QG, Zhou CF, Han D, Gulati P, Yang
LC, Yang F, Wang RM, Brann DW (2010) Role of
Rac1 GTPase in NADPH oxidase activation and cognitive
impairment following cerebral ischemia in the rat. PLoS
One 5, e12606.
Bongmba OY, Martinez LA, Elhardt ME, Butler K, TejadaSimon MV (2011) Modulation of dendritic spines and
synaptic function by Rac1: A possible link to Fragile X
syndrome pathology. Brain Res 1399, 79-95.
Ramakers GJ, Wolfer D, Rosenberger G, Kuchenbecker
K, Kreienkamp HJ, Prange-Kiel J, Rune G, Richter K,
Langnaese K, Masneuf S, Bosl MR, Fischer KD, Krugers
HJ, Lipp HP, van GE, Kutsche K (2012) Dysregulation
of Rho GTPases in the alphaPix/Arhgef6 mouse model of
X-linked intellectual disability is paralleled by impaired
structural and synaptic plasticity and cognitive deficits.
Hum Mol Genet 21, 268-286.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
[1649]
[1650]
[1651]
[1652]
[1653]
[1654]
[1655]
[1656]
[1657]
[1658]
[1659]
[1660]
[1661]
[1662]
[1663]
Borrelli S, Musilli M, Martino A, Diana G (2013)
Long-lasting efficacy of the cognitive enhancer Cytotoxic
Necrotizing Factor 1. Neuropharmacology 61, 74-80.
Desire L, Bourdin J, Loiseau N, Peillon H, Picard V, De
Oliveira C, Bachelot F, Leblond B, Taverne T, Beausoleil
E, Lacombe S, Drouin D, Schweighoffer F (2005) RAC1
inhibition targets amyloid precursor protein processing by
gamma-secretase and decreases Abeta production in vitro
and in vivo. J Biol Chem 280, 37516-37525.
Shutes A, Onesto C, Picard V, Leblond B, Schweighoffer
F, Der CJ (2007) Specificity and mechanism of action of
EHT 1864, a novel small molecule inhibitor of Rac family
small GTPases. J Biol Chem 282, 35666-35678.
Onesto C, Shutes A, Picard V, Schweighoffer F, Der
CJ (2008) Characterization of EHT 1864, a novel small
molecule inhibitor of Rac family small GTPases. Methods
Enzymol 439, 111-129.
Mans RA, McMahon LL, Li L (2012) Simvastatinmediated enhancement of long-term potentiation is driven
by farnesyl-pyrophosphate depletion and inhibition of farnesylation. Neuroscience 202, 1-9.
Gagnon KT (2010) HD Therapeutics - CHDI Fifth Annual
Conference. IDrugs 13, 219-223.
Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers
E, Shea TB (2001) Homocysteine potentiates beta-amyloid
neurotoxicity: Role of oxidative stress. J Neurochem 78,
249-253.
Shea TB, Ashline D, Ortiz D, Milhalik S, Rogers E
(2004) The S-adenosyl homocysteine hydrolase inhibitor
3-deaza-adenosine prevents oxidative damage and cognitive impairment following folate and vitamin E deprivation
in a murine model of age-related, oxidative stressinduced neurodegeneration. Neuromolecular Med 5, 171180.
Anekonda TS, Reddy PH (2006) Neuronal protection by
sirtuins in Alzheimer’s disease. J Neurochem 96, 305-313.
Bonda DJ, Lee HG, Camins A, Pallas M, Casadesus G,
Smith MA, Zhu X (2011) The sirtuin pathway in ageing and Alzheimer disease: Mechanistic and therapeutic
considerations. Lancet Neurol 10, 275-279.
Baur JA, Sinclair DA (2006) Therapeutic potential of
resveratrol: The in vivo evidence. Nat Rev Drug Discov
5, 493-506.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C,
Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K,
Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang
M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG,
Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram
DK, de Cabo R, Sinclair DA (2006) Resveratrol improves
health and survival of mice on a high-calorie diet. Nature
444, 337-342.
Baur JA (2010) Resveratrol, sirtuins, and the promise of a
DR mimetic. Mech Ageing Dev 131, 261-269.
Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de Cabo
R, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand
SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh
C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P,
Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano
M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA,
Tong Q, Tsubota K, Vaquero A, Verdin E (2010) Dietary
restriction: Standing up for sirtuins. Science 329, 10121013.
Kennedy DO, Wightman EL, Reay JL, Lietz G, Okello
EJ, Wilde A, Haskell CF (2010) Effects of resveratrol on
cerebral blood flow variables and cognitive performance
[1664]
[1665]
[1666]
[1667]
[1668]
[1669]
[1670]
[1671]
[1672]
[1673]
[1674]
[1675]
[1676]
[1677]
657
in humans: A double-blind, placebo-controlled, crossover
investigation. Am J Clin Nutr 91, 1590-1597.
Quideau S, Deffieux D, Pouysegu L (2012) Resveratrol
still has something to say about aging! Angew Chem Int
Ed Engl 51, 6824-6826.
Marambaud P, Zhao H, Davies P (2005) Resveratrol
promotes clearance of Alzheimer’s disease amyloid-beta
peptides. J Biol Chem 280, 37377-37382.
Albani D, Polito L, Batelli S, De MS, Fracasso C, Martelli
G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro
A, Forloni G (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against
toxicity caused by alpha-synuclein or amyloid-beta (1-42)
peptide. J Neurochem 110, 1445-1456.
Albani D, Polito L, Forloni G (2010) Sirtuins as novel
targets for Alzheimer’s disease and other neurodegenerative disorders: Experimental and genetic evidence.
J Alzheimers Dis 19, 11-26.
Albani D, Polito L, Signorini A, Forloni G (2010)
Neuroprotective properties of resveratrol in different neurodegenerative disorders. Biofactors 36, 370-376.
Ladiwala AR, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, Tessier PM (2010) Resveratrol
selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem 285,
24228-24237.
Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan
L, Wang M (2009) Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 74,
619-624.
Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ,
Kang SS, Cho GJ, Choi WS, Roh GS (2012) Resveratrol attenuates obesity-associated peripheral and central
inflammation and improves memory deficit in mice fed a
high-fat diet. Diabetes 61, 1444-1454.
Johnson WD, Morrissey RL, Usborne AL, Kapetanovic
I, Crowell JA, Muzzio M, McCormick DL (2011)
Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring
polyphenol with cancer preventive activity. Food Chem
Toxicol 49, 3319-3327.
Zhang Y, Li SZ, Li J, Pan X, Cahoon RE, Jaworski JG,
Wang X, Jez JM, Chen F, Yu O (2006) Using unnatural protein fusions to engineer resveratrol biosynthesis in
yeast and Mammalian cells. J Am Chem Soc 128, 1303013031.
Pasinetti GM, Wang J, Marambaud P, Ferruzzi M, Gregor
P, Knable LA, Ho L (2011) Neuroprotective and metabolic
effects of resveratrol: Therapeutic implications for Huntington’s disease and other neurodegenerative disorders.
Exp Neurol 232, 1-6.
Stergiakouli E, Langley K, Williams H, Walters J,
Williams NM, Suren S, Giegling I, Wilkinson LS, Owen
MJ, O’Donovan MC, Rujescu D, Thapar A, Davies W
(2011) Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder. Genes Brain
Behav 10, 334-344.
Johnson DA, Rhodes ME, Boni RL, Li PK (1997)
Chronic steroid sulfatase inhibition by (p-O-sulfamoyl)-Ntetradecanoyl tyramine increases dehydroepiandrosterone
sulfate in whole brain. Life Sci 61, L-9.
Li PK, Rhodes ME, Burke AM, Johnson DA (1997)
Memory enhancement mediated by the steroid sulfatase
inhibitor (p-O-sulfamoyl)-N-tetradecanoyl tyramine. Life
Sci 60, L45-L51.
658
[1678]
[1679]
[1680]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes
Rhodes ME, Li PK, Burke AM, Johnson DA (1997)
Enhanced plasma DHEAS, brain acetylcholine and memory mediated by steroid sulfatase inhibition. Brain Res 773,
28-32.
Chu GH, Peters A, Selcer KW, Li PK (1999) Synthesis
and sulfatase inhibitory activities of (E)- and (Z)-4hydroxytamoxifen sulfamates. Bioorg Med Chem Lett 9,
141-144.
Wang DS, Uchikado H, Bennett DA, Schneider JA, Mufson EJ, Wu J, Dickson DW (2008) Cognitive performance
[1681]
correlates with cortical isopeptide immunoreactivity as
well as Alzheimer type pathology. J Alzheimers Dis 13,
53-66.
Walters BJ, Campbell SL, Chen PC, Taylor AP, Schroeder
DG, Dobrunz LE, Artavanis-Tsakonas K, Ploegh HL, Wilson JA, Cox GA, Wilson SM (2008) Differential effects of
Usp14 and Uch-L1 on the ubiquitin proteasome system
and synaptic activity. Mol Cell Neurosci 39, 539-548.