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Journal of Alzheimer’s Disease 34 (2013) 1–114
DOI 10.3233/JAD-121729
IOS Press
Review
Cognitive Enhancers (Nootropics). Part 3:
Drugs Interacting with Targets other than
Receptors or Enzymes. Disease-modifying
Drugs
Wolfgang Froestl∗ , Andrea Pfeifer and Andreas Muhs
AC Immune SA, EPFL, Lausanne, Switzerland
Accepted 7 October 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. The review covers the evolution of research in this field over the last 25 years.
Keywords: Amyloid-␤ aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products,
peptides, psychostimulants, tau, vaccines
INTRODUCTION
As of September 30, 2012, there are 26,788 entries
in PubMed under the term cognitive enhancers, 26,781
entries under the term nootropic, and 245 entries under
the term cognition enhancers. Scifinder lists 5,133
references under the research topic nootropic, 541
references under the term cognitive enhancer, and
9,853 references for cognition enhancers. The Thomson Reuters Pharma database lists 1,111 drugs as
∗ 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].
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.
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 (ADHD), 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
define cognition as “a suite of interrelated conscious
ISSN 1387-2877/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
(and unconscious) mental activities, including preattentional 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
the mechanism(s) of cognitive enhancers. Therefore,
we propose a new classification to assign cognition
enhancing drugs to 19 categories:
In Part 1, drugs interacting with receptors were
described [5]. In Part 2, drugs interacting with enzymes
were described [1696]. Here, in Part 3, we give an
overview on drugs interacting with targets 3 to 10 and
compounds and preparations of categories 11 to 19.
Disease modifying drugs are aimed to counteract the
progression of a disease. In particular for AD, many
excellent reviews discuss this subject (in chronological order) [6–27]. ␣-secretase activators and ␤- and
␥-secretase inhibitors (and modulators) were presented
in Part 2 of this review. Drugs interacting with amyloid␤ (A␤) and tau including immunotherapy are described
in Part 3.
DRUGS INTERACTING WITH CYTOKINES
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)
There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS)
contribute to cognitive impairment via cytokinemediated interactions between neurons and glial cells.
A current hypothesis is that an extracellular insult
to neurons could trigger the production of inflammatory cytokines by astrocytes and microglia [28].
Conversely, A␤ has been shown to induce the expression of interleukin (IL)-1␤, tumor necrosis factor-␣
(TNF-␣) and IL-6 in astrocytes and microglia in culture [29]. One genome-wide analysis in 691 subjects of
mean age of 72.6 years showed that raised chemokine
(C-C motif) receptor 2 (CCR2) expression was the
most strongly associated transcript with lower MiniMental Status Exam scores and accelerated decline in
score over a period of 9 years [30]. Decline in score
over a period of 9 years [30]. The expression profiles of
cytokines in the brains of Alzheimer’s disease patients
were compared to the brains of non-demented patients
[1697]. Also see 11. Antioxidants, Also see 11. Antioxidants, because inflammation is tightly connected with
the oxidative cascade.
TT-301 (MW01-6-189WH; MW-189; Transition
Therapeutics, Toronto following its acquisition of NeuroMedix under license from Northwestern University)
is an inhibitor of microglial cell activation and proinflammatory cytokine production for the potential i.v.
treatment of CNS diseases including AD. Preclinical
characterization of the suppression of brain proinflammatory cytokine upregulation was carried out [31]. A
double-blind, randomized, placebo-controlled Phase I
clinical trial in healthy male subjects (n = 16) started
in the US in May 2011 (Thomson Reuters Pharma,
update of September 14, 2012). The structure was not
communicated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
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Fig. 1. Drugs interacting with cytokines and with gene expression.
TT-302 (MW01-7-084WH, MW-084; Transition
Therapeutics, Toronto; Fig. 1) is an inhibitor of proinflammatory cytokine production by activated glia for
the potential oral treatment of CNS disorders including
AD, traumatic brain injury and inflammatory diseases
such as arthritis [32]. Phase I clinical trials are expected
for 2012 (Thomson Reuters Pharma, update of September 29, 2012).
Minozac (MW01-2-151SRM, MW-151, Transition
Therapeutics, Toronto following its acquisition of NeuroMedix, under license from Northwestern University)
(Fig. 1) is an inhibitor of pro-inflammatory cytokine
production by activated glia for the potential treatment
of CNS diseases including AD, Parkinson’s disease
(PD), multiple sclerosis, and traumatic brain injury
[33–36] (Thomson Reuters Pharma, update of August
13, 2012).
AD-16 (Guangzhou Institutes of Biomedicine and
Health) is the thiophene analogue of Minozac. It
reduced amyloid-␤ induced spatial learning and memory impairment as potently as donepezil in an
Alzheimer’s mouse model [1698]. (Thomson Reuters
Pharma, update of October 19, 2012).
SEN-1176 (Senexis, Cambridge, UK) (Fig. 1) is a
pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine, which
suppresses A␤42 -induced macrophage production of
nitric oxide, TNF-␣, IL-1␤, and IL-6 in a dosedependent fashion, an activity profile consistent with a
neuroinflammation inhibitor [1711] (Thomson Reuters
Pharma, update of June 24, 2011).
Infliximab (Janssen Biotech, Horsham, PA),
a launched monoclonal antibody against TNF-␣,
improved cognition after intrathecal administration in
a woman with AD [38].
The University of Zurich is investigating an antibody
against the interleukin-12 subunit p40 for the potential treatment of Alzheimer’s disease [1699] (Thomson
Reuters Pharma, update of November 26, 2012).
The development of REN-1189 (formerly CPI1189; Centaur Pharmaceuticals), a TNF-␣ release
inhibitor, was terminated. Also the development of
Semapimod (CNI-1493; Cytokine PharmaSciences,
CPSI, formerly Cytokine Networks), a cytokine
inhibitor, which inhibited A␤ production, plaque formation, and cognitive deterioration in an animal model
of AD was suspended [39, 40].
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DRUGS INTERACTING WITH GENE
EXPRESSION
Gene therapy in AD, a potential for disease modification, was discussed [1715]. An interesting review
on genes and the parsing of cognitive processes was
communicated [42]. Bi-phasic change in brain-derived
neurotropic factor (BDNF) gene expression following antidepressant drug treatment was described [43,
44]. The modulation of Nur77 and Nor-1 expression
by dopaminergic drugs was elucidated [45]. The regulation of GABAA receptor subunit expression by
pharmacological agents was investigated [46]. Gene
therapy in mouse models of Huntington’s disease (HD)
was reviewed [47].
Beperminogene perplasmid (AMG-0001; DS992; Collategene; AnGes MG, formerly MedGene
Bioscience, Osaka, in collaboration with Daiichi
Sankyo) is a hepatocyte growth factor (HGF)
plasmid-based gene therapy for i.m. injection. It
showed nootropic properties with a potential for the
treatment of PD. In November 2011, a Phase III trial
for peripheral arterial disease was expected to be initiated in 2012. In April 2012, the Phase III studies were
still in preparation [48]. A long-term follow-up evaluation of results from the clinical trial TREAT-HGF
was reported [49] (Thomson Reuters Pharma, update
of September 19, 2012).
RVX-208 (Resverlogix, Calgary) (Fig. 1) is an
apolipoprotein A1 (ApoA1) gene expression stimulator for the potential prevention of A␤ plaque
accumulation in AD. In January 2011, data from an
analysis of AD biomarkers in the Phase II ASSERT
trial in 299 patients showed that after 12 weeks
of treatment with 150 mg/day, a positive effect on
A␤40 was seen. A compilation of data on RVX-208
was published in Drugs in R & D [50]. The rationale for the SUSTAIN study (172 patients) and the
ASSURE study (310 patients) was presented [51].
Preclinical evaluations were reported [52, 53] and
clinical data were provided [54–56]. RVX-208 significantly increased high-density lipoprotein (HDL)-C
(p = 0.001), the primary endpoint of the SUSTAIN trial,
a Phase 2b clinical study. SUSTAIN also successfully
met secondary endpoints, showed increases in levels of
Apo-AI (p = 0.002) and large HDL particles (p = 0.02),
both believed to be important factors in enhancing
reverse cholesterol transport activity. In July 2012, the
company was planning to initiate a Phase II trial of
RVX-208 in patients with mild cognitive impairment
(MCI) in the second half of 2013 (Thomson Reuters
Pharma, update of September 27, 2012).
There are several drugs interacting with gene expression in preclinical evaluation (in alphabetical order):
AAV-CYP46A1 (INSERM in collaboration with
sanofi) is an adeno-associated virus (AAV) 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 APP23 mice. Significant
improvements in cognitive function assessed by the
Morris water maze were seen in Tau22 mice [57]
(Thomson Reuters Pharma, update of June 6, 2012).
See also Part 2, Chapter 2.12. Drugs interacting with
cholesterol 24-hydroxylase (CYP46A1).
AZ-AAV9 (RegenX Biosciences, Washington DC)
is an AAV vector-9 that carries neuroprotective genes
for the potential injectable treatment of AD (Thomson
Reuters Pharma, update of July 27, 2012).
HSD17B10 is a gene, which encodes HSD10, a
mitochondrial multifunctional enzyme that plays a
significant part in the metabolism of neuroactive
steroids and the degradation of isoleucine. Elevated
levels of HSD10 were observed in the hippocampi of
AD patients [58].
PRO-289 (Prosensa Therapeutics, Leiden, the
Netherlands) is the lead from a series of single-stranded
RNA-based antisense oligonucleotide-based therapeutics to inhibit the CTG trinucleotide repeat expansion
of the huntingtin gene (HTT) by preventing the cellular production of aberrantly expanded HTT mRNA and
mutant huntingtin protein (Thomson Reuters Pharma,
update of February 10, 2012).
SynCav (Raft Therapeutics, San Diego CA) is
a gene therapy that upregulates synaptic driven
Caveolin-1 to promote regeneration of neurons for
the potential treatment of neurodegenerative diseases
such as AD, PD, HD, and amyotrophic lateral sclerosis
(ALS) (Thomson Reuters Pharma, update of August
10, 2012).
Intrahippocampal gene transfer of F-spondin, an
activator of the reelin pathway, improved spatial learning/memory in the Morris water maze and increased
the exploration of the novel object in the Novel Object
Recognition test in wild-type mice [59].
lnventiva (Daix, Bourgogne, France) is investigating compounds that increase expression of a target gene
under epigenetic control resulting in increased levels of
a secreted neuronal protein for the potential treatment
of Alzheimer’s disease. (Thomson Reuters Pharma,
update of November 23, 2012). Structures were not
communicated.
Neurologix under license from Keio University was
investigating colivelin, a hybrid peptide composed of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
activity-dependent neurotrophic factor [60–64] and a
humanin derivative for the potential gene therapy
of AD [65, 66]. The program was terminated. The
development of LX-6171 (Lexicon Pharmaceuticals,
formerly Lexicon Genetics), a small molecule inhibitor
of the SLC6A gene and the LG617 receptor, was discontinued as well.
DRUGS INTERACTING WITH HEAT
SHOCK PROTEINS
Binding of heat shock protein 90 (HsP90) to tau
facilitates a conformational change that results in
its phosphorylation by glycogen synthase kinase 3␤
(GSK-3␤) and its aggregation into filamentous structures [67]. HsP90 regulates tau pathology through
co-chaperone complexes [68].
HsP90 inhibitors, such as PU-H71, PU-3, PU24FCl
(Fig. 2) and PU-DZ8 of the purine class of HsP90
inhibitors from the Memorial Sloan-Kettering Institute
of Cancer Research, New York caused an elimination
of aggregated tau [69–75].
5
PU-H71 is in Phase I clinical trials since July 2011
(n = 40) in the US. The study was expected to be complete by July 2013 (Thomson Reuters Pharma, update
of April 24, 2012).
ALS Biopharma (Doylestown, PA) is investigating
small-molecule brain-penetrant modulators of HsP70
for the potential treatment of neurological disorders
including AD (Thomson Reuters Pharma update of
January 17, 2012).
Conforma Therapeutics (San Diego, CA) presented
a new class of HsP90 inhibitors [76–78] and showed
that E102 (structure not disclosed) promoted selective decrease of the P-tau species in a mouse model
of tauopathy.
KU-32 (University of Kansas, Fig. 2) is a novobiocin derivative acting as an inhibitor of Hsp90 and an
inducer of Hsp70 for the potential treatment of neurological diseases. In transgenic mice expressing human
P301L-mutant tau KU-32 (10 mg/kg for 15 weeks)
reduced cortical levels of CP13-Iabeled tau [1700].
(Thomson Reuters Pharma, update of May 31, 2012).
Lundbeck follows up another series of HsP90
inhibitors (Thomson Reuters Pharma update of March
31, 2011).The structures were not disclosed.
Fig. 2. Heat shock protein 90 inhibitors and a thyrotropin-releasing hormone analogue.
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A␤ accumulation decreased expression of the heat
shock-protein 70-interacting protein (CHIP), which
functions as a tau ubiquitin ligase [79]. CHIP is a
key molecular link between A␤ and tau pathologies. Increasing CHIP levels may have beneficial
effects to decrease tau pathology, because CHIP can
polyubiquitinate tau and may play a crucial role in
preventing accumulation of phospho-tau and neurofibrillary tangles. Heat shock protein 70 prevented both
tau aggregation and the inhibitory effect of preexisting tau aggregates on fast axonal transport [80]. An
exchange of HsP70 for HsP90 is involved in tau degradation [1701].
Excellent reviews on heat shock proteins were previously published [81, 82].
The development of AEG-33773 (Aegera Therapeutics), an allosteric modulator of HsP90 leading to
HsP70 upregulation, was terminated.
DRUGS INTERACTING WITH HORMONES
Sustained efforts went into the exploration of the
cognition enhancing effects of thyrotropin-releasing
hormone and its analogues since it had been recognized as an activator of brain cholinergic systems [83].
Pilot studies of intravenous thyrotropin-releasing hormone in AD were undertaken [84, 85]. Improvement of
cognitive deficits in depressed patients were reported
[86].
Taltirelin (Ceredist, TA-0910; Mitsubishi Tanabe
Pharma) (Fig. 2), an orally active synthetic thyrotropinreleasing hormone analogue, was launched in Japan in
2000 for the treatment of neurodegenerative disease, in
particular spinocerebellar degeneration [87–89]. The
sales in 2011 were USD 226.8 million (Thomson
Reuters Pharma, update of August 30, 2012).
KPS-0373 (Kissei under license from Shionogi)
is a thyrotropin-releasing hormone derivative for the
potential oral treatment of spinocerebellar ataxia in
Phase II clinical trials in Japan (Thomson Reuters
Pharma, update of July 31, 2012). The structure was
not communicated.
Leuprolide acetate implant (VP-4896, Memryte;
Curaxis Pharmaceuticals, Raleigh NC, formerly Voyager Pharmaceutical and DURECT) is a biodegradable
implant formulation of the gonadotropin-releasing
hormone agonist 1-9-luteinizing hormone-releasing
factor-6D-leucine-9-(N-ethyl-L-prolinamide), a nonapeptide, for the treatment of AD in women. A
Phase IIb clinical study plan is currently evaluated. The effects of treatment with leuprolide acetate
depot on working memory in women were described
[90]. Luteinizing hormone modulated the processing of amyloid-␤ protein precursor (A␤PP) and
A␤ deposition [91] and of cognition in transgenic
mice [92]. Several reviews were published [93–96]
(Thomson Reuters Pharma, update of August 24,
2012).
Tesamorelin (Egrifta; TH-9507; Theratechnologies, Quebec and US commercialization partner EMD
Serono and licensee Sanofi) is a stabilized, truncated growth hormone releasing factor (GRF1-44;
ThGRF1-44). In a controlled study of 152 adults (66
with MCI) participants self-administered daily subcutaneous injections of tesamorelin or placebo for 20
weeks, which had favorable effects on cognition in both
adults with MCI and healthy older adults [97] (Thomson Reuters Pharma, update of August 15, 2012).
The development of azetirelin (YM-14673;
Yamanouchi, now Astellas [98, 99]), of calcitriol (Neurocalc; Apollo Biopharmaceuticals,
now MitoKor), of JTP-2942 (Japan Tobacco
[100–102]), of montirelin (CG-3703; CNK-602A;
NS-3; Grünenthal [103]), of orotirelin (CG-3509;
Grünenthal [104–106]), of posatirelin (RGH-2202;
Gedeon Richter [107–109]), of protirelin (DN-1417;
Takeda [110]), of thyrotropin-releasing hormone
analogs (Roche), and of thymoliberin (RX-77368;
Reckitt & Colman [111]) was terminated.
DRUGS INTERACTING WITH ION
CHANNELS (NON-RECEPTORS)
Dysregulation of Ca2+ homeostasis plays a crucial
role in the pathogenesis of AD. In the pathogenesis of AD [1702]. Oligomeric A␤ proteins directly
incorporated into neuronal membranes, formed cationsensitive ion channels (“amyloid channels”) and
caused disruption of calcium homeostasis [112, 113].
A␤ oligomers directly and dose-dependently modulated P/Q-type calcium channels [114]. In triple
transgenic AD mice, upregulated ryanodine receptor
activity led to a reduction of long-term potentiation
[115]. Mutations of presenilin can affect the intracellular calcium levels via the endoplasmic reticulum
calcium stores [116]. The levels of the calcium-sensing
enzyme hippocalcin were elevated in AD brains [117].
Interesting reviews were published [118–121].
Drug repositioning for the treatment of Alzheimer’s
disease was described recently [1703].
ARC-029 (Archer Pharmaceuticals, Roskamp Institute, Sarasota FL) is a blood-brain barrier crossing
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
7
Fig. 3. Two ion channel blocker and three NGF and BDNF stimulators.
formulation of nilvadipine (Fig. 3), a blocker of
L-type voltage-gated calcium channels. The drug has
been approved for a multisite Phase III clinical trial
enrolling more than 500 AD patients in Europe. In
February 2012, the study was expected to begin in the
second half of 2012 (Thomson Reuters Pharma, update
of April 16, 2012).
Nilvadipine (FR-34235; Fujisawa; launched in
Japan in 1989) was extensively characterized in vitro
and in vivo for the potential treatment of AD. It facilitated the clearance of A␤ across the blood-brain barrier
[122, 123]. It prevented the impairment of spatial memory induced by cerebral ischemia combined with A␤
in rats [124, 125]. It also antagonized A␤ vasoactivity [126]. First positive clinical results on nilvadipine
in AD patients were communicated. It was safe and
provided short-term cognitive benefits in AD patients
[127–131].
ARC-031 and ARC-031-SR (Archer Pharmaceuticals; sustained release formulation) is a non-calcium
channel blocking and soluble A␤ reducing nilvadipine
derivative in Phase I clinical trials (Thomson Reuters
Pharma, update of January 3, 2012). The structure was
not communicated.
RNS-60 (Revalesio Corporation, Tacoma WA) acts
on voltage-gated ion channels. It is formulated as
an inhalant anti-inflammatory charge-stabilized nanostructure. The company investigates also the potential
treatment in AD and PD. A Phase I/IIa asthma trial
began in May 2010. In October 2011, data from the
multi-dose stage of the Phase I study were reported.
RNS-60 showed a therapeutic benefit and was safe at
all doses (Thomson Reuters Pharma, update of April
27, 2012). The structure was not communicated.
ZSET-1446 (ST-101, Sonexa Therapeutics, San
Diego CA under license from Zenyaku Kogyo) (Fig. 3)
is in Phase II clinical trials for AD since February 2009.
A second Phase II clinical trial for the treatment of
essential tremor was initiated in the US in May 2011.
It was recognized that ZSET-1446 (ST-101) targeted
T-type voltage-gated calcium channels in mediating
improved cognition in the CNS [132]. In vivo data were
published previously [133, 134] (Thomson Reuters
Pharma, update of July 17, 2012).
AD-N02 (Adamed, Mazowieckie, Poland) is a
sodium channel blocker and dopamine/5-HT stabilizer
for the potential treatment of schizophrenia and bipolar
disorder (Thomson Reuters Pharma, update of August
22, 2012). The structure was not communicated.
Isradipine (Novartis, launched in 1997) is a
L-type voltage-gated calcium channel blocker protecting MC65 neuroblastoma cells from A␤PP
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C-terminal fragment (A␤PP-CTF)-induced neurotoxicity [135–137, 1704].
The development of many drugs interacting with
ion channels was terminated (in alphabetical order):
DMP-543 (Bristol-Myers Squibb; an inhibitor of Mtype K+ channels), enecadin (PAION under license
from Nippon Shinyaku; a sodium and calcium channel
blocker), LB-101, LB-102, LB-217, LB-218, LB-253,
LB-269, LB-301, and LB-302 (Lifelike Biomatic;
modulators of two ionic channels, i.e., ionokines),
linopirdine (DuP 996; Du Pont Merck, Bristol-Myers
Squibb; an inhibitor of M-type K+ channels; despite
promising EEG brain mapping data [138] and an
increase of parietal regional cerebral blood flow in
AD patients [139], the clinical results were disappointing [140]), MEM-1003 (BAY-Z-4406, Memory
Pharmaceuticals under license from Bayer; a L-type
voltage-gated calcium channel [141]), nerispirdine
(HP-184, Hoechst, now sanofi; an inhibitor of Mtype K+ channels), nicardipine (YC-93, Yamanouchi
[142]), nifedipine (BAY-A-1040, Adalat, Bayer
[143]), nimodipine (BAY-E-9736, Nimotop, Bayer
[144–152]), nitrendipine (BAY-E-5009; Bayotensin,
Bayer; all L-type voltage-gated calcium channels
[153, 154]), NP-34 (NP-04634; Noscira, formerly
Neuropharma; a dual calcium channel blocker and
acetylcholinesterase inhibitor [155]), NS-649 (NeuroSearch; a neuron-specific calcium channel blocker
[156]), NSD-761 (NeuroSearch; a selective ion channel modulator); RGH-2716 (TDN-345; a nootropic
neuroselective ion channel blocker; Takeda in collaboration with Gedeon Richter [157–159]), SNX-482
(R-type calcium channel blocker of Neurex, now
Elan Pharmaceuticals [160–162]), SPI-017 (Sucampo;
selective type-2 chloride channel activator), tamolarizine (NC-1100, calcium channel blocker, Nippon
Chemiphar [163–165]), VRX-698 (Valeant Pharmaceuticals International; a potassium channel opener),
and XE-991 (Bristol-Myers Squibb; a KCNQ potassium channel blocker [166, 167]).
DRUGS INTERACTING WITH NERVE
GROWTH FACTORS
The role of neurotrophic factors in AD was discussed [168] as was a neurotrophic rationale for
the therapy of neurodegenerative diseases [169]. The
potential therapeutic use of BDNF, a key regulator
for protein-synthesis dependent long-term potentiation
and long-term memory, in neurological and psychiatric
disorders was presented [170, 171], in particular for
AD [172, 173]. Interestingly, genetic knockdown of
BDNF in triple transgenic AD mice did not alter A␤
or tau pathology [174]. Nerve growth factor (NGF)cholinergic dependency in brain aging, MCI, and AD
was discussed [175–181]. NGF treatment in dementia was described [182]. NGF and AD, new facts
for an old hypotheses were communicated recently
[183]. Hippocampal ProNGF signaling pathways and
amyloid-␤ levels in mild cognitive impairment and
Alzheimer’s disease were elucidated [1705]. It was
claimed that NGF promoted long-term memory formation by activating poly(ADP-ribose) polymerase-1
(PARP-1) [184].
NeuroAid (MLC-601; Danqi Plantan Jiaonang;
Moleac Pte Ltd, Singapore) is a BDNF stimulator
derived from Radix Astragali, Radix Salvia Miltiorrhizae, Radix Paeoniae Rubra, Rhizoma Chuanxiong,
Radix Angelicae Sinensis, Carthamus Tinctorius,
Prunus Persica, Radix Polygalae, Rhizoma Acori
Tatarinowii, Buthus Martensii, Hirudo, Eupolyphaga
Seu Steleophaga, Calculus Bovis Synthetic or Artifactus and Cornu Saigae Tataricae, for the potential
oral prevention of stroke including cerebral infarction
and ischemic stroke and for the potential treatment
of traumatic brain injury in a randomized, doubleblind, placebo-controlled, multicenter, Phase III trial
(n = 1100) since November 2007 in Singapore and the
Philippines. The study was expected to be completed
in 2012 (Thomson Reuters Pharma, update of October
3, 2012).
CERE-110 (AAV2-NGF; NeuroRescue AD; Ceregene, San Diego CA) is an AAV2 vector based gene
delivery system containing cDNA for NGF. A Phase II
clinical trial in mild-to-moderate AD patients (n = 50)
started in May 2009 in the US. The therapeutic potential of CERE-110 was described in detail [185, 186]
(Thomson Reuters Pharma, update of July 20, 2012).
GM-607 (Genervon Biopharmaceuticals, Pasadena
CA) is a motoneuronotrophic factor analogue for the
potential treatment of ischemic stroke, spinal cord
injuries, ALS, AD, HD, and PD. By April 2011, a
Phase II ischemic stroke trial was initiated. By February 2012, further Phase II IND applications were
being prepared for spinal cord injuries, ALS, PD, and
AD (Thomson Reuters Pharma, update of August 28,
2012).
MIM-D3 (Mimetogen Pharmaceutics, Quebec,
Fig. 3) is a small molecule NGF peptidomimetic for
the treatment of AD and dry eye (xerophthalmia). A
Phase II trial for dry eye was initiated in November
2010 [187] (Thomson Reuters Pharma, update of May
17, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
PYM-50028 (Cogane, P58, P63; Phytopharm, UK)
(Fig. 3), a steroidal saponin, stimulated BDNF
release and may be beneficial for the treatment
of PD, AD, glaucoma, and ALS. PYM-50028
reversed neuronal damage induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MTPT) in a mouse
model of PD [188]. In July 2011, FDA granted
PYM-50028 orphan drug status for ALS. In November 2010, recruitment of patients (n = 400) began
in the randomized, double-blind, proof-of-concept,
placebo-controlled, dose-ranging Phase II study
CONFIDENT-PD (Thomson Reuters Pharma, update
of August 16, 2012).
T-817MA (Toyama Chemical, Fujifilm Holding)
(Fig. 3) is a neurotrophic small molecule in Phase
II clinical trials for AD in the US since April 2008.
T-817MA attenuated cognitive impairments in P301L
tau transgenic mice [189], prevented memory deficits
caused by i.c.v. A␤ administration [190, 191], and
attenuated A␤-induced neurotoxicity [192] (Thomson
Reuters Pharma, update of July 30, 2012).
NsG-0202 (ECB-AD, ECT-AD, NsGene A/s, Denmark) is an encapsulated cell biodelivery system to
deliver cells expressing NGF. A Phase Ib trial started
in December 2007 in Sweden. First clinical data were
presented in July 2011. In January 2012, the trial was
expected to be completed in 2012 [193] (Thomson
Reuters Pharma, update of January 17, 2012).
There are several drugs interacting with neurotrophic factors in preclinical evaluation (in alphabetical order):
AL-209 (ADNF-9, SAL; Allon Therapeutics, Vancouver) is an activity-dependent neurotrophic factor
derived nine amino acid sequence peptide and tubulinbinding agent that stimulated PARP-1 for the potential
treatment of CNS and ocular disorders (Thomson
Reuters Pharma, update of March 6, 2012).
AL-309 (Allon Therapeutics, Vancouver) is an
analogue of AL-209 and PARP stimulator for oral,
intranasal and s.c. administration. By October 2012
preclinical development had been completed (Thomson Reuters Pharma, update of October 17, 2012).
AMRS-001 (CNS-001; Amarantus BioSciences,
Sunnyvale CA, formerly CNS Protein Therapeutics
having acquired the relevant IP from Prescient Neuropharma) is a program of therapeutics based on
mesencephalic astrocyte-derived neurotrophic factor
[194], which promoted the survival of dopaminergic
neurons for the potential treatment of PD, AD, and
brain injury. It also protected the heart from ischemic
damage [195] (Thomson Reuters Pharma, update of
October 2, 2012).
9
Catecholamine derivatives (Emory University,
Atlanta, GA) acted like BDNF to activate the tyrosine
kinase B (TrkB) receptor. They have a potential for the
treatment of neurological diseases such as ALS, PD,
and AD (Thomson Reuters Pharma, update of July 27,
2012). Structures were not communicated.
CB-1, CB-2, and CB-3 (Molcode, Tartu, Estonia)
are BDNF mimetics, which activated the TrkB receptor leading to its phosphorylation (Thomson Reuters
Pharma, update of December 27, 2011). The structures
were not communicated.
7,8-Dihydroxy-flavone, a TrkB receptor agonist
and BDNF mimic, reversed memory deficits in a mouse
model of AD [196]. The compound and derivatives
thereof are also evaluated at Emory University in collaboration with the University of Wisconsin [197–199]
(Thomson Reuters Pharma, update of August 10,
2012).
FC29 peptide (University of Queensland, Brisbane,
Australia) is a fragment of the p75 neurotophin receptor that inhibited p75NTR-mediated neuronal death
via regulation of the Trk receptor function for the
potential treatment of AD, PD, and motor neuron disease (Thomson Reuters Pharma, update of May 17,
2012).
Gambogic amine and gambogic amide (Emory
University, Atlanta GA), TrkA receptor agonists with
robust neurotrophic activity, prevented neuronal cell
death [200] (Thomson Reuters Pharma, update of
August 28, 2012).
Gedunin (Emory University, Atlanta GA) and its
derivatives including deoxygedunin are TrkB receptor
agonists for the potential treatment of PD, HD, AD,
HIV-related dementia, ALS, stroke, and multiple sclerosis [201] (Thomson Reuters Pharma, update of April
26, 2012).
JRP-655 (Prous Institute for Biomedical Research,
Barcelona) is a BDNF secretagogue and neuroplasticity modulator (Thomson Reuters Pharma, update of
September 5, 2012). The structure was not communicated.
4-methylcatechol, which increased BDNF content
and stimulated BDNF mRNA expression and synthesis, effectively improved spatial learning and memory
in rats [202, 203].
NeuroAiD II (MLC-901, Moleac Pte Ltd., Singapore), a BDNF stimulator, is a derivative of NeuroAiD
for the potential treatment of global ischemia in
preclinical development (Thomson Reuters Pharma,
update of September 2, 2011).
ND-602 (Neurodyn, Charlottetown, Canada) is a
neuroprotective progranulin (PC cell-growth factor)-
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expressing lentiviral vector for the potential treatment
of PD, AD, and ALS. ND-602 was found to increase
activity of neprilysin and significantly reduced A␤ and
plaque burden in the hippocampus and entorhinal cortex of Tg2576 mice (Thomson Reuters, update of May
25, 2012).
The development of many drugs interacting with
neurotrophic factors was terminated. The most
advanced drug, xaliproden (SR-57746A, Xaprila;
sanofi), a 5-HT1A agonist and stimulator of endogenous neurotrophin synthesis, did not meet the cognition
endpoints in Phase III trials in AD patients, which
applies also to paliroden (SR-57667B; with a biphenyl
instead of the ␤-naphtyl in xaliproden; sanofi, [204]).
The lessons learnt from the xaliproden clinical trials
were discussed [205]. The biological characterization
was reviewed [206].
Also the development of other drugs interacting with neurotrophic factors (in alphabetical
order) was terminated: ABS-200 (American Biogenetic Sciences), ADNF-14 (NIH, activity-dependent
neurotrophic factor-14), AGT-120, and AGT-140
(ArmaGen Technologies); AK-30-NGF (a monoclonal antibody as carrier for the delivery of NGF;
Alkermes), arundic acid (MK-0724, ONO-2506, Arocyte, Ono Pharmaceuticals [207–210]), beta NGF
(tethered to a molecular shuttle; Apollo Life Sciences), CEP-427 (a neurotrophic factor enhancing
small molecule; Cephalon, now Teva), coleneuramide
(MCC-257; Mitsubishi Tanabe Pharma), CX-438
(Cortex Pharmaceuticals), dekafin-1 (a fibroblast
growth factor receptor, agonist and tyrosine kinase
modulator; Enkam Pharmaceuticals); dFGF (dimerized fibroblast growth factor; Massachusetts Institute
of Technology (MIT)/ViaCell Inc.), GDF-1 (Creative
Biomolecules, now Curis; a growth and differentiation factor-1 agonist), glial maturation factor
(Rhone-Poulenc/Regeneron), huIM-13 (a humanized
monoclonal antibody that binds to the TrkA receptor,
Lay Line Genomics), inosine (an NGF, Alseres Pharmaceuticals, formerly Boston Life Sciences (BLSI),
under license from the Children’s Hospital of Boston),
KP-66, KP-447, and KP-546 (Krenitsky), leteprinim
(AIT-082; SPI-205, Neotrofin; Spectrum Pharmaceuticals, formerly NeoTherapeutics), which induced the
expression of NGF, neurotrophin-3, and of basic
fibroblast growth factor [211–216], LM11A-31 (a p75
neurotrophin receptor ligand; Elan), nerve growth
factor agonists (Chiron), neuregulin-2 (cerebellumderived growth factor, NRG2; Acorda Therapeutics
under license from CeNeS and Harvard University), NGF therapy (Lay Line Genomics), NP-901
(Noscira), NS-521 (NeuroSearch), p75 NGF receptor antagonist (Circadian Technologies under license
from the Walter & Eliza Hall Institute), NT-3 (Genentech and StemCells), ReN-1820 (ReNeuron under
license from the University of Bristol), ST-857 (acetylL-carnitine arginine amide; Sigma-Tau [217–219]),
T-588 (Toyama [220–227]), and trofexin (a peptide
neurotrophic factor; Protarga).
DRUGS INTERACTING WITH RE-UPTAKE
TRANSPORTERS (PSYCHOSTIMULANTS)
Psychostimulants exert behavioral-calming and
cognition-enhancing actions in the treatment of ADHD
[228]. Cognition-enhancing doses of psychostimulants
exert regionally restricted actions elevating extracellular catecholamine levels and enhancing neural
signal processing preferentially in the prefrontal cortex. Additional evidence suggests a prominent role of
prefrontal cortex ␣2 and D1 receptors in the behavioral and electrophysiological actions of low-dose
psychostimulants [229, 230]. Excellent reviews on
attention-modulating effects of cognitive enhancers
were published [231–236]. An analysis of student
use (and abuse) of cognitive enhancers was presented
[237]. A review on glycine transporter type 1 (GlyT1)
inhibitors was disclosed [238].
Methylphenidate (Ritalin, Ciba, now Novartis, launched 1956) is a psychostimulant drug,
which increased the levels of dopamine and noradrenaline in the brain through re-uptake inhibition of
the monoamine transporters [239]. Methylphenidate
preferentially increased catecholamine neurotransmission within the prefrontal cortex at low doses
that enhance cognitive functions [240]. Cognitionenhancing doses of methylphenidate preferentially
increased prefrontal cortex neuronal responsiveness
[241]. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task
[242]. The improvement of memory functions by
methylphenidate (and modafinil) in healthy individuals
was described [243].
Most of these experiments were made with
the mixture of erythro and threo stereoisomers.
The active principle of methylphenidate is the
(+)-(␣R,2R)-threo-methylphenidate
hydrochloride
(Dexmethylphenidate, Ritadex; Novartis Pharma
under license from Celgene launched 2002) (Fig. 4),
also available as an extended-release oral formulation
Focalin XR [244]. The spheroidal oral drug absorption system dexmethylphenidate was described [245]
(Thomson Reuters Pharma, update of July 27, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
11
Fig. 4. Psychostimulant cognition enhancers.
Modafinil (Provigil, Lafon Laboratories, later
Cephalon, now Teva, launched 1998) is an inhibitor of
dopamine, noradrenaline, and serotonin re-uptake and
an ␣1 adrenoceptor agonist [246]. Modafinil showed
improvement of cognition and attention in patients
with chronic schizophrenia ADHD [247, 248], in particular in the first episode of psychosis [249, 250]. The
neuronal mechanism by which modafinil affects cognitive and emotional function in schizophrenic patients
was reviewed [251]. Experiments using BOLD functional magnetic resonance imaging (fMRI) in healthy
volunteers showed that modafinil enhanced the efficiency of prefrontal cortical cognitive information
processing, while dampening reactivity to threatening
stimuli in the amygdala, the brain area implicated in
anxiety [252]. Modafinil improved attention in wellrested individuals [243]. Modafinil reliably enhanced
performance on several cognitive tests of planning
12
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
and working memory, but did not improve learning
and delayed recall performance in healthy volunteers
[253]. It may be useful in the treatment of substance
abuse [254]. It improved working memory and sustained attention in cocaine users [255].
The active principle of modafinil is the (R)enantiomer Armodafinil (Nuvigil; CEP-10953;
Cephalon, now Teva launched 2009) (Fig. 4). The
sales of armodafinil in 2011 amounted to USD 266
mil (Thomson Reuters Pharma, update of September
21, 2012).
Atomoxetine (tomoxetine, Strattera, LY-139603;
Lilly; launched 2003) (Fig. 4) is a selective noradrenaline re-uptake inhibitor for the treatment of
ADHD in children and adults [256]. Atomoxetine
inhibited noradrenaline and serotonin transporters with
Ki values of 2.6 and 48 nM, respectively [257]. Atomoxetine improved response inhibition in ADHD
patients and in healthy volunteers via increased activation in the right frontal gyrus measured via fMRI
[258, 259]. Sales in 2011 were USD 620 million
(Thomson Reuters Pharma, update of September 26,
2012).
Lisdexamfetamine (Vyvanse; Shire Pharmaceuticals and New River Pharmaceuticals, launched 2007)
(Fig. 4) is a drug for the treatment of ADHD in
children, adolescents, and adults [260]. Lisdexamfetamine itself is inactive and acts as a prodrug to
dextroamphetamine upon cleavage of the lysine portion of the molecule. Dextroamphetamine inhibited
noradrenaline, serotonin and dopamine transporters
with respective Ki values of 39, 3,830, and 34 nM
[261]. The use of lisdexamfetamine in patients with
dementia was described [231]. Sales in 2011 were
USD 805 million (Thomson Reuters Pharma, update
of September 28, 2012).
Indeloxazine
(YM-08054;
Elen,
Noin,
Yamanouchi, Schering-Plough, now Merck and
Jeil Pharmaceuticals, launched in China and South
Korea) (Fig. 4) blocked the reuptake of noradrenaline
with IC50 of 3.2 ␮M and of serotonin with IC50 of
0.71 ␮M. It is also a MAO inhibitor. It showed learning
and memory improving effects in many animal tests
[262–267].
NS-2359 (NeuroSearch, Fig. 4) is a blocker of
dopamine, noradrenaline, and serotonin re-uptake currently in Phase I clinical trials in Denmark for
the potential treatment of CNS diseases. GSK was
previously developing NS-2359 for the treatment
for depression but discontinued the development
(Thomson Reuters Pharma, update of September 26,
2012).
There are several drugs interacting with re-uptake
transporters in preclinical evaluation (in alphabetical
order):
AM-285 (Cyclocreatine, CincY; Lumos Pharma,
Austin TX based on University of Cincinnati technology) (Fig. 4) is evaluated for the potential treatment
of creatine transporter deficiency, an X-linked autism
spectrum disorder characterized by severe cognitive
impairment [268]. In June 2012, the FDA awarded
cyclocreatine Orphan designation for the treatment
of creatine transporter deficiency (Thomson Reuters
Pharma, update of August 24, 2012).
AS-1522489-00 (Astellas Pharma) is a glycine
transporter-1 inhibitor, a 1,2,4-triazole derivative, of
which only the (S)-atropisomer is biologically active
[269, 270] (Thomson Reuters Pharma, update of January 27, 2012). The structure was not communicated.
Lu-AA42202 (Lundbeck) (Fig. 4) is a triple
dopamine, noradrenaline, and serotonin re-uptake
inhibitor for the potential treatment of major depressive disorders and ADHD (Thomson Reuters Pharma,
update of December 1, 2010).
MLR-1017 (mesocarb, sydnocarb, sidnocarb,
Melior Pharmaceuticals, Exton, PA) (Fig. 4) is
a dopamine transporter inhibitor for the potential
treatment of ADHD and levodopa-induced side effects
in PD. The drug was previously launched in Russia
[271, 272] (Thomson Reuters Pharma, update of April
12, 2012).
PD-2005 (P2D Bioscience, Cincinnati, OH, identical with AHN 2-005, National Institute of Drug Abuse
and US Naval Medical Research Center) (Fig. 4) is an
inhibitor of the dopamine transporter for the potential
treatment of ADHD and for cognitive impairments in
traumatic brain injury. It dose-dependently improved
performance of rats in a delayed-alternation task of
spatial working memory [273] (Thomson Reuters
Pharma, update of June 12, 2012).
RO-4543338 (Roche) is a well-tolerated glycine
transporter inhibitor, which facilitated drug cue extinction [274, 275]. The structure was not communicated.
Selective Serotonin Re-uptake Inhibitors (SSRIs)
showed cognitive enhancing effects [276]. Patients
treated with citalopram showed significant improvements on a cognitive subscale. Paroxetine and fluoxetine improved most of the tested cognitive functions in
a study of 242 depressed patients during one year [277].
Other studies with citalopram, fluoxetine, sertraline,
and zimelidine did not report improvement of memory
and/or reaction time in demented patients [278].
Thiethylperazine (Torecan) (Fig. 4), a drug
approved by the FDA to relieve nausea and vomiting,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
13
Fig. 5. VMAT2 and DA-reuptake PET ligands.
is an activator of ABCC1 transporters. In a mouse
model of AD expressing the ABCC1 transporter, a
markedly reduced load of A␤ was measured. Deficiency of ABCC1 transporter substantially increased
cerebral A␤ levels [279] (Thomson Reuters Pharma,
update of April 26, 2012).
The development of ASP-2535 (Astellas; a
glycine transporter-1 inhibitor [280]), coluracetam
(BCI-540, MKC-231; BrainCells Inc. under license
from Mitsubishi Tanabe Pharma; an enhancer of
high-affinity choline uptake and K+ -induced release
of acetylcholine [281–288]), CP-101 (CogniPharm,
an i.v. formulation of modafinil), D-serine re-uptake
inhibitors (Memory Pharmaceuticals, now Roche),
flufenoxina (FAES Farma; a dual serotonin and norepinephrine re-uptake inhibitor), glycine transporter-1
inhibitors (Helicon Therapeutics), JNJ-17305600
(NFPS; NPS Allelix; a glycine transporter inhibitor
[289]), PD-2007 (P2D Bioscience, a dopamine transporter inhibitor), SCH-900435 (Org-25935; Organon,
Schering-Plough, now Merck, a glycine transporter-1
inhibitor), SSR-103800 [290–292]) and SSR-504734
(both sanofi; both glycine transporter-1 inhibitors
[293–297]), teniloxazine (sufoxazine, Lucelan,
Metatone, Y-8894, Yoshitomi, Mitsubishi Pharma, a
noradrenaline uptake inhibitor [298],[299–301]), and
tesofensine (NS-2330, NeuroSearch, a monoamine
re-uptake inhibitors of serotonin, dopamine, and noradrenaline [302]) was terminated. The development
of tesofensine for the once-daily oral treatment of
obesity in Phase II trials was also suspended [303].
The vesicular monoamine transporter 2
(VMAT2) located on the membrane of vesicles
is responsible for storing and packaging neurotransmitters into monoamine vesicles or granules.
Imaging VMAT2 in the brain provides a measurement
reflecting the integrity of dopaminergic, noradrenergic
and serotonergic neurons [304]. Positron emission
tomography (PET) ligands for the VMAT2 have
become valuable diagnostic tools.
(+)-[11 C]-dihydrotetrabenazine (DTBZ) (Fig. 5)
allows the determination of the striatal monoaminergic
presynaptic terminal density. In a study enrolling 20
patients with dementia with Lewy bodies (DLB), 25
AD patients, 7 patients with frontotemporal dementia,
and 19 elderly controls clinicians could accurately
differentiate between the different forms of dementia
[305–307]. The uptake of (+)-11 C-DTBZ in the stria-
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
tum of AD patients mainly reflecting the presynaptic
dopaminergic system was unchanged compared to
controls. The striatal uptake in DLB and PD patients
was significantly decreased [308].
18 F-Florbenazine (18 F-AV-133; 18 F-FP-DTBZ;
Avid Radiopharmaceuticals, Philadelphia PA, a subsidiary of Lilly, under license from University of
Michigan) (Fig. 5) is in Phase III clinical evaluation.
In May 2012, an open-label, single-blind, Phase II/III
study (NCT01550484; 18 F-AV-133-B04) was initiated in patients with undiagnosed movement disorders
(n = 150) in the US to assess the safety and efficacy
of florbenazine in differentiating PD. At that time, the
study was scheduled to complete in September 2014.
For the synthesis, see [309]; for the binding characteristics in rat striatum and hypothalamus homogenates
(Kd = 0.19 and 0.25 nM, respectively), see [310, 311].
The whole body biodistribution was studied [312].
18 F-AV-133 was used for noninvasive assessment of
the vesicular monoamine transporter type 2 in 17 PD
patients and 6 healthy controls. VMAT2 binding potential was decreased by 81% in the posterior putamen,
70% in the anterior putamen, and 48% in the caudate
nucleus of PD patients [313].
This ligand is a valid measure of dopaminergic
neuron integrity. The in vivo assessment in patients
with DLB and AD was reported [314]. The optimal
scanning time window was elucidated [315]. For PET
imaging in a MPTP-induced mouse model of PD, see
[316] (Thomson Reuters Pharma, update of August 7,
2012).
11 C-␤-CFT and 18 F-␤-CFT (Fig. 5) proved to
be valuable PET ligands due to their high affinity
interaction with dopamine re-uptake sites. AD patients
showed a reduction of 11 C-␤-CFT in putamen and caudate of about 20%. Thus the putamen and the caudate
nucleus were equally affected in contrast to PD, which
showed predominantly putaminal reduction [317]. In
PD, the mean uptake of 18 F-␤-CFT in the contralateral putamen was reduced to 31% and in the ipsilatral
putamen to 45%. In the caudate nucleus, the uptake
was reduced contralaterally to 67% and ipsilaterally to
77% [318]. For an exhaustive review, see [319].
123 I-Ioflupane (123 I-FP-CIT; Amersham, now GE
Healthcare) (Fig. 5) is a SPECT ligand launched in
2000. It is the ligand of choice to differentiate between
AD and DLB patients [320, 321]. It is valuable for
the diagnosis of Parkinsonian syndromes [322]. SERT
dependent 123 I-ioflupane uptake allows a more comprehensive assessment of neurochemical disturbances
in degenerative Parkinsonism [323–325] (Thomson
Reuters Pharma, update of August 14, 2012).
DRUGS INTERACTING WITH
TRANSCRIPTION FACTORS
cAMP response element-binding (CREB) protein
and the discovery of cognitive enhancers was reviewed
[326–328]. CREB phosphorylation as a mechanistic marker in the development of memory enhancing
AD therapeutics was described [329]. The current
knowledge of key calcium signal-regulated transcription factors, namely CREB, nuclear factor of activated
T-cells, and downstream regulatory element antagonist modulator (DREAM) and memory formation was
summarized [330]. A␤ disrupted activity-dependent
gene transcription required for memory through the
CREB-regulated transcription co-activators CRTC1
[331]. The GABAB receptor antagonist SGS742
improved spatial memory and reduced protein binding to CREB2 in the hippocampus [332] (see Part
1, Chapter 1.10.2 GABAB receptors). CREB antisense oligonucleotide administration into the dorsal
hippocampal CA3 region impaired long- but not shortterm spatial memory in mice [333].
The lack of DREAM protein enhanced learning and
memory and slowed brain aging [334].
SRF/MYOCD inhibitors (Socratech LLC,
Rochester NY) are small molecule inhibitors against
serum response factor and myocardin, which are
interactive transcription factors in vascular smooth
muscle cells for the potential treatment of AD
[335]. For a review on the imbalance of vascular
molecules in AD, see [336] (Thomson Reuters
Pharma, update of February 15, 2012). Structures
were not communicated.
The development of CREB modulators (Helicon
Therapeutics) and of EPAC inhibitors (exchange protein directly activated by cAMP, a guanine nucleotideexchange factor; Scottish Biomedical [337]) was
terminated.
ANTIOXIDANTS
Soluble A␤ oligomers localize to mitochondria
and interfere with their normal functioning causing an overproduction of reactive oxygen species
(ROS), inhibiting respiration and ATP production and
damaging the structure of mitochondria [338–340].
Some authors, however, claim that the early impairments of mitochondrial dysfunction and oxidative
stress may precede A␤ overproduction and deposition [341–343]. Excellent reviews were presented
over years [344–347]. Possibilities of intervention of
antioxidant pathways in AD were discussed [348, 349].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
15
Fig. 6. Mitochondria-targeting antioxidants.
Also see Chapter 3. Cytokines, as inflammation is
tightly connected with the oxidative cascade.
Over the years, clinicians have explored treatment
of AD patients with antioxidants. Free radicals can
be scavenged by dietary means. Compounds such as
acetyl-L-carnitine, curcumin [350], Gingko biloba
extracts such as EGb 716, (R)-α-lipoic acid, melatonin, morin, trolox, vitamin C [351], and vitamin E
[352–355] were tested in clinical trials in AD patients.
The results were disappointing [356–372]. As a consequence of a landmark study, clinicians even advise AD
patients not to take large doses of vitamin E or ␣-lipoic
acid [373].
Many clinical trials were also carried out with
synthetic antioxidants such as edaravone (MCI-186,
Mitsubishi [374],[375–377]), idebenone (CV-2619,
Avan, Catena, Noben, Sovrima; Takeda [378–380]),
and the derivatives of 21-aminosteroids (Upjohn’s
lazaroids, such as tirilazad or U-74006F, U-74389G,
U-74500A, U-75412E, U-78518F, and U-83836E
[381–384]). None of these compounds produced statistically significant therapeutic benefits for AD patients.
MitoQ (redox mixture of mitoquinone and mitoquinol; Antipodean Pharmaceuticals, Menlo Park
CA, under license from the University of Otago;
Fig. 6 shows the oxidized form) is a brain penetrating mitochondria-targeting antioxidant [385–388]. It
selectively blocked mitochondrial oxidative damage
and prevented cell death [389–394]. It is evaluated in
Phase II clinical trials for the treatment of PD and liver
damage. Clinical trials for the treatment of Friedreich’s
ataxia and sunburn were abandoned (Thomson Reuters
Pharma, update of June 18, 2012).
A potential follow-up compound is MitoVitE
(Fig. 6) [395, 396]. The development of MitoPBN
(Antipodean Pharmaceuticals, Menlo Park CA)
(Fig. 6) consisting of the spin trapping agent ␣phenyl-N-tert.-butyl-nitrone [397, 398] conjugated to
triphenyl-phosphonium bromide was terminated [399]
(Thomson Reuters Pharma, update of June 18, 2012).
MTP-131 (Bendavia, SS-31, Szeto-Schiller peptide; Stealth Peptides Inc., Newton Centre MA) (Fig. 7)
is a cell-permeable mitochondria-targeting antioxidant
tetrapeptide (NH2 -D-Arg-Dmt-Lys-Phe-NH2 ), which
is in Phase II clinical trials for ischemia reperfusion
injury since September. 2010 (EMBRACE–STEMI
trial). It will further be investigated for the treatment
of eye, neurological, mitochondrial, and metabolic
16
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Fig. 7. The Szeto-Schiller peptide, a manganoporphyrin antioxidant and CNB-001.
diseases [400–402],[403] (Thomson Reuters Pharma,
update of June 15, 2012).
VP-20629 (OX1; IN-OX1; OX1; OXIGON, Indole3-propionic acid; ViroPharma, Exton PA, under license
from Intellect Neurosciences, New York University
and Mindset BioPharmaceuticals) is an antioxidant and
A␤ aggregation/deposition inhibitor. The prevention of
A␤ induced neurotoxicity by indole-3-propionic acid
was described [404]. The rationale behind the selection
of OXIGON as a potential disease-modifying therapy
for Alzheimer’s disease was presented [1706]. Preliminary data from a multiple-dose Phase Ib trial for
AD were reported in October 2010. It appears that
ViroPharma wants to pursue the drug for the indication
Friedreich’s ataxia only (Thomson Reuters Pharma,
update of August 17, 2012).
There are several antioxidants in preclinical evaluation (in alphabetical order):
Catalytic manganoporphyrine antioxidants, such
as AEOL-10113, AEOL-10150, AEOL-10201 and
AEOL-11207 (Aeolus Pharmaceuticals, Mission
Viejo CA; Fig. 7) may be promising for the treatment of
PD and ALS [405–407] and ischemic stroke [408–412]
(Thomson Reuters Pharma, update of April 23, 2012).
CNB-001 (The Salk Institute for Biological Studies)
(Fig. 7) is a curcumin derivative for potential treatment
of traumatic brain injury and stroke (Thomson Reuters
Pharma, update of November 9, 2011).
DL-3-n-butylphtalide (NBP, Hebei, China) is a natural antioxidant extracted from seeds of Apium and
a powerful free radical scavenger [413]. It protected
dopamine neurons in a rotenone model for PD [414].
FRP-0924 (gemifloxacin, Neuron BioPharma,
Granada, Spain) is an antioxidant and neuroprotectant
for the potential treatment of neurodegenerative diseases including AD. FRP-924 crossed the blood-brain
barrier and prevented neuronal death. As fluoroquinolones are generally well tolerated with most side
effects being mild and serious adverse effects being
rare, it is expected that the drug will enter Phase II
rapidly (Thomson Reuters Pharma, update of August
14, 2012).
IAC (Cerebricon, Finland and Medestea Research,
Torino, Italy) (Fig. 8) is a novel radical scavenger react-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
17
Fig. 8. Antioxidants in preclinical evaluation.
ing with most carbon-, nitrogen-, and oxygen-centered
radicals of biological interest [415–418]. Daily treatment with IAC (3–30 mg/kg i.p.) decreased mortality,
enhanced cognitive functions in the water maze, and
reduced the A␤ plaque burden in hA␤PP transgenic
mice [419].
Lipid soluble antioxidants (OXIS International,
Beverley Hills CA) mimic the activity of the body’s
natural cell membrane-protecting antioxidant vitamin
E for the potential treatment of cardiovascular diseases,
diabetes, AD, and PD (Thomson Reuters Pharma,
update of June 12, 2012). The structures were not
communicated.
Lipocrine and Memoquin, dual acetylcholinesterase inhibitors and antioxidants (University of
Bologna), were described in Part 2, Chapter 2.1.1.3.
(formulae in Part 2 in Fig. 6).
NPS-0155 (Neuron BioPharma, Granada, Spain) is
an antioxidant and neuroprotective compound for the
potential treatment of AD and other neurodegenerative
diseases (Thomson Reuters Pharma, update of April
27, 2012). The structure was not communicated.
PAN-811 (3-AP; NSC-663249; OCX-191; Triapine,
Panacea Pharmaceuticals, Gaithersburg MD) (Fig. 8) is
a ribonucleotide reductase inhibitor, calcium ion chelator, and radical scavenger for the potential treatment
of AD and ischemia [420, 421] (Thomson Reuters
Pharma, update of February 25, 2011).
S-52 (Shanghai Institute of Materia Medica) (Fig. 8)
is a sinomenine derivative, an active natural product
from the Chinese herb Sinomenum acutum. It is a scavenger of free radicals. It attenuated the toxicity of A␤
to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain
[422].
There are numerous preclinical reports of drugs
and natural products, which, in addition to their radical scavenging properties, also prevented A␤-induced
neurotoxicity, such as peoniflorin [423], 2,2 -pyridoin
[424], quetiapine [425]), stemazole (Fig. 8) [426], and
zeatin (Fig. 8) [427].
Dual free radical scavengers and A␤ binding ligands were described [428, 429].
The development of many antioxidants was terminated (in alphabetical order) of AN-808 (Athena
Neurosciences, now Elan Pharmaceuticals), AO-2 and
AO-3 antioxidants (Antoxis), CNSB-002 (AM-36;
Relevare; AMRAD, formerly Zenyth Therapeutics
[430] [431, 432]), CPI-1189 (Centaur [433, 434]), disufenton sodium (Cerovive, NXY-059, AstraZeneca,
which was in Phase III clinical trials for the treatment
of acute ischemic stroke [435–445]), FR-210575 (Fujisawa [446]), MDL-101002 (Hoechst Marion Roussel,
now sanofi [447, 448]), and raxofelast (IRFI-016,
Biomedica Foscama Industria [449–452]).
METAL CHELATORS
The metallobiology of AD was investigated in great
detail over the last fifteen years. Excellent reviews were
18
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
published (in chronological order) 2001: [453], 2002:
[454], 2003: [455], 2006: [456], 2007: [457–459],
2008: [460–462], 2009: [463–467], 2010: [468–472],
2011: [473–478], 2012: [479–485], 2012: [1707].
DP-b99 (D-Pharm, Rehovot, Israel) (Fig. 9) is an
i.v. prodrug of the calcium and zinc chelator BAPTA
for the potential treatment of stroke and traumatic
brain injury. It is in Phase III clinical trials for stroke
since October 2009. First reports on clinical results
were communicated [486–488]. Also preclincial data
were disclosed [489–491] (Thomson Reuters Pharma,
update of February 3, 2012).
PBT-2 (Prana Biotechnology, Parkville, Australia)
(Fig. 9) is an oral zinc ionophore metal-protein attenuating compound that reduced levels of soluble A␤ and
tau hyperphosphorylation [492]. A Phase IIa study in
AD patients (n = 78), started in December 2006 with
daily doses of 50 or 250 mg or placebo over three
months, was completed in January 2008. A significant reduction of A␤42 levels in the cerebrospinal fluid
(CSF) was seen in the 250 mg group. This dose also
significantly improved executive function performance
in the category fluency and the trail making cognitive tests compared to placebo [493, 494]. In January
2012, the FDA approved an IND to initiate a randomized, multicenter, double-blind, placebo-controlled,
parallel-group, safety, tolerability, and efficacy Phase
IIa trial in early- to mid-stage HD patients (n = 100) in
the US and Australia. In April 2012, the first patient
was dosed in this trial. By June 2012 the trial had
been initiated in Australia. Data are expected in the
second half of 2013. The compound was extensively
characterized in preclinical studies [495–497] (Thomson Reuters Pharma, update of October 2, 2012). See
also Chapter 17.1. Small molecules preventing tau
aggregation.
AEN-100 (Synthetic Biologics, formerly Adeona
Pharmaceuticals, Ann Arbor, MI) is a once-daily, gastroretentive, sustained-release, oral tablet formulation
of zinc acetate for the potential treatment of ALS and
AD. By November 2011, a Phase I study for ALS
patients was underway (Thomson Reuters Pharma,
update of September 19, 2012).
Other metal chelators are currently in preclinical
evaluation (in alphabetical order):
Aom-0937 (Hangzhou Adamerck Pharmlabs,
China) is a prodrug of DP-b99 (Thomson Reuters
Pharma, update of July 28, 2011). The structure was
not communicated.
DP-460 (D-Pharm, Rehovot Israel) (Fig. 9) is a
membrane active chelator derivative of the calciumspecific chelator BAPTA that modulates copper and
zinc homeostasis to inhibit oxygen radicals and plaque
formation. It is in preclinical evaluation for the potential oral treatment of AD and ALS (Thomson Reuters
Pharma, update of November 1, 2011). It appears that
DP-460 was preferred to DP-109 [498]. Both compounds have been evaluated as neuroprotectants in
a transgenic mouse model of ALS [499] (Thomson
Reuters Pharma, update of August 7, 2012).
Deferoxamine (SAN-121; Sanomune, a subsidiary
of DiaMedica under license from HealthPartners
Research Foundation, Winnipeg, Canada) (Fig. 10) is a
nasally-delivered iron chelator improving performance
in a radial arm water maze in P3301L tau transgenic mice [500] (Thomson Reuters Pharma, update
of December 23, 2011).
HLA20A (Technion Haifa) (Fig. 10) is a combination of an 8-hydroxy-quinoline metal chelator,
which was carbamoylated at the 8-hydroxy function
to interact with acetylcholinesterase as in rivastigmine
[501, 502]. See Part 2, Chapter 2.1.1.10. Dual acetylcholinesterase inhibitors and metal chelators.
PA-1637 (Palumed, France) is an A␤ plaque
production-inhibiting copper chelating agent (Thomson Reuters Pharma, update of May 28, 2012). The
structure was not communicated.
PBT-3 and PBT-4 (Prana Biotechnology, Parkville,
Australia) are non-8-hydroxyquinoline metal protein attenuating compounds, potential follow-ups of
PBT-2. (For both Thomson Reuters Pharma, update
of November 2, 2011). The structures were not
communicated.
Triazole-pyridine derivatives as inhibitors of
metal-induced A␤ aggregation were described [503].
VAR-10200 (HLA-20; Varinel, West Chester, PA)
(Fig. 10) is a dual iron-chelating agent and MAO-B
inhibitor for the potential treatment of age-related macular degeneration [501] (Thomson Reuters Pharma,
update of February 24, 2012). See Part 2, Chapter 2.26.
Drugs interacting with Monoamine Oxidase.
VAR-10300 (M-30; Varinel, West Chester, PA,
Technion and the Weizmann Institute) (Fig. 10)
combines the iron-chelating properties of 8-hydroxyquinoline with the MAO inhibitor moiety of rasaglinine
[504–517] (Thomson Reuters Pharma, update of
September 24, 2012). See also Part 2, Chapter 2.26.
Drugs interacting with Monoamine Oxidase.
The development of many metal chelators was
terminated (in alphabetical order): desferrioxamine [518–520], Gero-46 (clioquinol, Gerolymatos);
NG-1 and PBT-1 (clioquinol, Prana Biotechnology [521, 522]); phanquinone (PN Gerolymatos);
tetrathiomolybdate (a copper chelating agent of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
19
Fig. 9. Metal chelators.
Fig. 10. Metal chelators II.
Adeona Pharmaceuticals, formerly Pipex under license
from the University of Michigan); the iron chelator
VAR-10100 (VK-28) [523–526] and VK-11 and VK12 (Prana Biotechnology).
NATURAL PRODUCTS
Excellent reviews on naturally occurring phytochemicals for the prevention and treatment of AD have
20
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
been presented [527–532]. An overview on “natural
substances and AD: from preclinical studies to evidence based medicine” was published recently [533].
Mentat (BR-16A; Himalaya Drug Co.) is a standardized mixture of herbal extracts, which has been
launched in India and the US (as MindCare) in
November 2000 for the treatment of cognitive deficits
(Thomson Reuters Pharma, update of November 6,
2000).
YY-280 (Yucrid; Yuyu, South Korea) is a combination therapy of ticlopidine and EGb-761 (tanamin,
a Ginkgo biloba extract) administered as a tablet
for the treatment of apoplexy and myocardial infarction. The drug was registered in Korea in May 2008
[534] (Thomson Reuters Pharma, update of April 11,
2012).
SK-PC-B70M (SK Chemicals Life Science, South
Korea) is derived from the dried root of Pulsatella
koreana (baekduong). A randomized, double-blind,
placebo-controlled Phase III clinical trial for the treatment of mild-to-moderate AD patients (n = 256) was
initiated in November 2010 in South Korea. SK-PCB70M improved scopolamine-induced impairments of
memory consolidation in rats [535, 536]. It had antioxidant activity and reduced A␤ levels in the brains of
Tg2576 mice [537, 538]. It alleviated the neurologic
symptoms in G93A-SOD1 ALS mice [538] (Thomson
Reuters Pharma, update of February 28, 2012).
Circadin (KI-1001, NSC-56423; Neurim Pharmaceuticals, Tel Aviv) is an oral controlled-release
formulation of melatonin (i.e., melatonin acetamide)
and was launched in 2007 for the treatment of primary
insomnia. A Phase II clinical trial was initiated in Israel
in patients with MCI (n = 50) in October 2007. Another
Phase II clinical trial was initiated in the US, UK, and
Israel in patients with mild-to-moderate AD (n = 140)
treated with an acetylcholinesterase inhibitor to evaluate the effects of add-on Circadin (2 mg) on decline in
cognitive skills, global functioning, and daytime somnolence in September 2009 (Thomson Reuters Pharma,
update of September 26, 2012).
KD-501 (Kwang Dong Pharmaceutical Co., Seoul)
is an extract from the Scrophulariae radix. The drug is
in Phase II clinical trials for AD since March 2009
(Thomson Reuters Pharma, update of February 11,
2011).
PPLs (NatureWise Biotech, Taipeh, Taiwan) are
prenylflavanone compounds extracted from Taiwanese
propolis in Phase II clinical trials. A pilot AD program
of PPLs in combination with Aricept was initiated in
November 2010 (Thomson Reuters Pharma, update of
July 10, 2012).
PTX-200 (Phytrix, Munich, Germany) is a plantderived neuroprotectant for the potential treatment of
PD. A Phase I/IIa clinical evaluation in the UK was
successfully completed (Thomson Reuters Pharma,
update of February 1, 2012).
Resveratrol is a natural phyto compound, which
activated Sirtuin-1 [539–544]. It reduced A␤ accumulation [545–548]. It remodeled soluble oligomers
and fibrils of A␤ into off-pathway conformers [549].
Resveratrol is not a direct activator of SIRT1 enzyme
activity [550]. Resveratrol improved memory deficits
in mice fed a high-fat diet [551]. Subchronic oral
toxicity and cardiovascular safety pharmacology studies were carried out [552]. The biosynthesis of
resveratrol in yeast and in mammalian cells was
achieved [553]. The Georgetown University Medical
Center in Washington DC started at Phase II, randomized, double-blind, placebo-controlled study in
patients with mild-to-moderate AD (n = 120) in the US
in May 2012 (NCT01504854). A novel application in
HD was discussed recently [554]. See also in Part 2,
Chapter 2.40, Drugs interacting with Sirtuin, formula
in Part 2, Fig. 23 (Thomson Reuters Pharma, update of
June 22, 2012).
RPh-201 (Regenera Pharma, Rehovot, Israel) is a
subcutaneous formulation of an agent derived from
a traditional medicinal plant. A Phase I/IIa randomized, double-blind, placebo-controlled trial in healthy
volunteers and adults with AD (n = 56) started in January 2012 in Canada. A topical formulation is currently
evaluated in a Phase II study in patients with chronic
ulcerated wounds (n = 15) in Israel (both Thomson
Reuters Pharma, update of January 31, 2012).
VR-040 (apomorphine as dry powder inhaled
formulation, Vectura, Chippenham, UK) is being
developed in Phase II clinical trials for the potential
treatment of PD since June 2006 (Thomson Reuters
Pharma, update of October 3, 2012).
Exebryl-1 (ProteoTech, Kirkland, WA and Chinese
licensee Tasly Pharmaceuticals) is a synthetic compound with molecular weight of about 300 Da, one of
the components of an Amazonian vine Uncaria tomentosa extract, which reduced aggregation of both A␤
and tau. A Phase I clinical trial for AD was initiated in
July 2008 (Thomson Reuters Pharma, update of June
8, 2012).
Taisi (Beijing SL Pharmaceutical under license from
Xuanwu Hospital of Capital Medical University), a
capsule formulation of a stilbene analogue isolated
from an unspecified organism, is in clinical studies in
China since February 2011 (Thomson Reuters Pharma,
update of June 29, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
There are many natural products in preclinical evaluation as potential drugs for the treatment of AD (in
alphabetical order):
Alpha-mangostin, a polyphenolic xanthone derivative from mangosteen, concentration-dependently
attenuated neurotoxicity induced by A␤1-40 or A␤1-42
oligomers (EC50 = 3.89 nM and 4.14 nM, respectively)
[555].
Anatabine (Star Scientific, Glen Allen VI through
its subsidiary Rock Creek Pharmaceuticals in collaboration with the Roskamp Institute) reduced A␤
when applied to cells [556] (Thomson Reuters Pharma,
update of January 3, 2012).
Andrographis paniculata leaves extract showed
cerebroprotective and nootropic activities in rats [557].
Apomorphine is an inhibitor of A␤ fibril formation
[558]. Apomorphine treatment of AD mice promoted
A␤ degradation [559]. Roles of apomorphine for regulated ␣-cleavage, autophagy, and antioxidation were
discussed [560].
AX-00111 (Axonal Consultoria Tecnologica Ltda,
Sao Paulo Brazil) is a plant-derived compound for the
potential treatment of AD (Thomson Reuters Pharma,
update of June 1, 2012).
Axona (Accera Inc., Broomfield, CO) is a new
medical food therapy for AD patients [561, 562].
It contains the proprietary formulation of mediumchain triglycerides, mostly caprylic triglyceride. The
rationale for the use of Axona is based on the finding that the cerebral hypometabolism (i.e., impaired
glucose metabolism) is an early sign of AD. Mediumchain triglycerides are metabolized in the liver
resulting in the production of the ketone body betahydroxybutyrate, which is transported to the brain
to provide an alternative fuel source for cerebral
metabolism [563, 564]. See also [565].
Bacopa monnieri has shown memory free recall
enhancing effects in adult humans [566]. Neuroprotective effects in experimental models of dementia were
described [567].
Baicalein (5,6,7-trihydroxyflavone) protected cortical neurons from A␤25-35 -induced toxicity [568] and
in a one dose pre-treatment at 5 and 10 mg/kg i.p.
attenuated A␤25-35 -induced amnesia in mice in a stepthrough passive avoidance paradigm. Post-treatment
for 7 or 13 days (10–15 mg/kg i.p.) also attenuated
A␤25-35 -induced amnesia [569]. Baicalin prevented
the production of hydrogen peroxide and oxidative
stress induced by A␤ aggregation in SH-SY5Y cells
[570]. Apigenin (4 ,5,7-trihydroxyflavone), baicalein,
and nordihydroguaiaretic acid were potent inhibitors
of liposome permeabilization by A␤42 oligomers
21
[571]. Baicalein inhibited the formation of ␣-synuclein
oligomers within living cells and prevented A␤ peptide
fibrillization and oligomerization [572].
Beta-asarone improved cognitive functions in rats
after injection of A␤ into the hippocampus [573] probably via JNK signaling and modulation of bcl-2 family
proteins [574] and attenuation of neuronal apoptosis
[575, 1708].
BT-11 is an extract of the dried root of Polygala tenuifolia (Willdenow) and effectively enhanced
cognitive functions in elderly humans [576–578].
BV-7003 (Bioved Pharmaceuticals) is a natural
product for the potential treatment of memory loss
(Thomson Reuters Pharma, update of September 11,
2012). The structure was not communicated.
Cabernet Sauvignon attenuated A␤ neuropathology in a mouse model of AD [579].
Carvacrol showed cognition enhancing activity in
two rat models of dementia [580].
Catechins showed potent anti-amyloidogenic and
fibril-destabilizing effects in vitro [581–583].
Celastrol, a triterpenoid antioxidant compound isolated from the Chinese Thunder of God vine (T.
wilfordii) reduced A␤ pathology in a transgenic mouse
model of AD [584].
Celastrus paniculatus seeds showed nootropic
activity [585].
Chelerythrine showed promising cholinesterase
inhibition, good inhibition of amyloid-␤ aggregation
and the ability to disaggregate preformed amyloid-␤
aggregates [1709].
Cinnamon extract reduced A␤ oligomerization and
corrected cognitive impairment in animal models of
AD [586].
Coumarins are naturally occurring ␤-secretase
inhibitors [587] and acetylcholinesterase inhibitors
[588].
Cryptotanshinone (CTS), an active component
of the medicinal herb Salvia miltiorrhiza, inhibited
A␤ aggregation and protected SH-SY5Y cells from
damage by A␤ [589]. It upregulated ␣-secretase by
activation PI3K pathway in cortical neurons [590].
Curcumin showed potent anti-amyloidogenic
effects for AD A␤ fibrils in vitro and in vivo [591–605].
Clinical trials in AD patients showed disappointing
results [350, 600, 606]. A novel nanoparticle formulation of curcumin (NanoCurc) was developed at
the Indiana University School of Medicine [607].
For curcumin-decorated nanoliposomes see [608].
Structure-activity relationships of A␤ aggregation
inhibitors based on the curcumin scaffold were presented [609–611].
22
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
DL-3-n-butylphtalide (NBP Pharmaceuticals,
Hebei China) is a natural antioxidant extracted from
seeds of Apium and a powerful free radical scavenger
[413]. It protected dopamine neurons in a rotenone
model for PD [414].
DX-9386 is a traditional Chinese medicinal
prescription, which improved thymectomy-induced
impairment of learning behaviors in mice [612].
Ecdysterones, steroidal hormones in insects and
terrestrial plants, inhibited A␤ aggregation, disaggregated preformed fibrils, and inhibited A␤42 -induced
cytotoxicity [613].
(-)-Epigallocatechin-3-gallate (EGCG; Sunphenon) present in green tea reduced A␤-mediated
cognitive impairment presumably via flavonoidmediated presenilin-1 phosphorylation, which
reduced A␤ production [614–616]. EGCG prevented
lipopolysaccharide-induced elevation of A␤ generation [617]. EGCG remodeled mature ␣-synuclein
and A␤ fibrils and reduced cellular toxicity [618].
The cell signaling pathways and iron chelation were
described [582, 619–624]. Also ERK and NF- κB
pathways are involved [617]. The structural properties
of EGCG-induced, nontoxic AD A␤ oligomers were
described [625]. EGCG functions through estrogen
receptor mediated activation of ADAM10 in the
promotion of non-amyloidogenic processing of A␤PP
[626, 627]). A special formulation of EGCG in
nanolipidic particles to improve its bioavailability was
presented [628]. See also Part 1, Chapter 1.9. Drugs
interacting with estrogen receptors and Part 1, Fig. 10.
ESP-102, a standardized combined extract of
Angelica gigas, Saururus chinensis, and Schizandra
chinenis, significantly improved scopolamine-induced
memory impairment [629] and A␤1-42 -induced memory impairment in mice [630].
An aqueous extract of Eucommia ulmoides
Oliv. Bark (EUE) showed beneficial effects on learning and memory impairments in mice [631].
Flavonoids in AD and neuroinflammation were
discussed in depth [621, 632–635]. Some act as acetylcholinesterase inhibitors [636]. Biflavanoids were
superior to monoflavonoids in inhibiting A␤ toxicity
[637].
Fortasyn Connect is a multi-nutrient diet comprising docosahexanoic acid (DHA), eicosapentenoic
acid, uridine-mono-phosphate, choline, phospholipids,
folic acid, vitamins B6, B12, C, and E and selenium. It reduced AD-like pathology in young adult
A␤PPSWE /PS1dE9 mice [638].
Fulvic acid inhibited aggregation and promoted disassembly of tau fibrils associated with AD [639].
Gallic acid from grape seed polyphenol extract may
be useful for the treatment of AD [583].
Garlic extract attenuated the cytotoxicity of A␤ on
undifferentiated PC12 cells [640] and suppressed lipid
peroxidation induced by A␤ in PC12 cells [641]. It
protected against A␤-induced apoptosis [642]. Garlic
extract inhibited A␤ fibril formation and defibrillated
A␤ preformed fibrils [643]. Aged garlic extract ameliorated the early cognitive deficits in Tg2576 mice
[644, 645]. A review on the “aged garlic extract” was
published [646].
Gastrodin protected primary cultured rat hippocampal neurons against amyloid-␤ peptide-induced
neurotoxicity via ERK1/2-Nrf2 pathway [1710].
Ginger root extracts (Zingiber officinale, Cognition Therapeutics) effected inhibition of A␤42
aggregation (Thomson Reuters Pharma, update of May
23, 2012).
Gingko biloba (EGb 761, Tanakan, Tanamin) treatment prevented age-related spatial memory deficits in
a transgenic mouse model of AD [647]. It enhanced
adult hippocampal neurogenesis and phosphorylation
of CREB [648]. For reviews on Ginkgo biloba extract
and CNS functions, see [649, 650]. For results of clinical studies, see (in chronological order) [651–665].
Grape-derived polyphenolics from Vitis vinifera
grape seeds attenuated cognitive deterioration in a
mouse model of AD [666]. Ultrastructural alterations
of AD paired helical filaments by grape seed-derived
polyphenols was studied [667].
Guanosine protected human neuroblastoma cells
from oxidative stress and toxicity induced by A␤ peptide oligomers [668].
Hederacolchidide-E from Pulsatilla koreana
showed cognition-enhancing and neuroprotective
effects by reversing scopolamine-induced cognitive
impairments in rats. It increased viability of human
neuroblastoma SK-N-SH cells incubated with A␤42
[536].
Heme prevented A␤1-40 aggregation and its cytotoxicity [669].
Hopeahainol A attenuated memory deficits by targeting amyloid-␤ in APP/PS1 transgenic mice [1711].
HSH-971 (Ocean University of China, Shandong)
is a marine sulfated oligosaccharide for the potential
treatment of AD [670]. (Thomson Reuters Pharma,
update of November 7, 2011).
HX-106 (HX-106N; ViroMed Co., Seoul) is a
natural product inhibiting acetyl-cholinesterase for
the potential treatment of AD (Thomson Reuters
Pharma, update of June 13, 2012). The structure was
not disclosed.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Hyperoside protected primary rat cortical neurons from neurotoxicity induced by A␤ via the
PI3K/Akt/Bad/Bcl(XL)-regulated
mitochondrial
apoptotic pathway [671].
IB-10C179(Instituto Biomar, Leon, Spain) is a
compound derived from marine organisms which protected primary neurons from apoptosis and reduced
free radical production (Thomson Reuters Pharma,
update of March 7, 2012). The structure was not
communicated.
Icariin is a flavonoid isolated from Epimedii
herba. It inhibited A␤25-35 induced expression of
␤-secretase in rat hippocampus [672]. It attenuated
A␤-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells [673]. It
attenuated lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting
TAK1/IKK/NF-κB and JNK/p38 MAPK pathways
[674]. It improved memory impairment in AD model
mice and attenuated A␤-induced neurite atrophy [675].
There seems to be a synergistic effect to improve learning and memory deficits in rats by co-administration
of Icariin and Panax notoginseng saponins [676].
IDN-5706, a hyperforin derivative, decreased the
content of acetylcholinesterase 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 [677].
Kaempferol protected PC12 and T47D cells from
A␤ toxicity [581, 678, 679].
Loganin isolated from Cornus officinalis showed
cognitive-enhancing activity in scopolamine-induced
amnesic mice [680].
Luteolin exerted ameliorating effects on A␤induced impairment of water maze performance and
passive avoidance in rats [681–684].
Medical Food Cocktail consisting of the dietary
supplements curcumin, piperine, epigallocatechin gallate, ␣-lipoic acid, N-acetylcysteine, B vitamins,
vitamin C, and folate administered for 6 months to
Tg2576 mice resulted in improvement of cognitive
functioning [685].
Melatonin inhibited AD ␤-fibrillogenesis
[686–689]. The neuro-protective activities of
melatonin against the A␤ are not mediated by melatonin membrane receptors. The role of melatonin in
AD-like neurodegeneration was described [690–693].
Melatonin facilitated short-term memory [694].
Menthol exerted a protective effect on A␤-induced
cognitive deficits in mice [695].
Morin destabilized A␤42 protofibrils [696]. It inhibited the early stages of A␤ aggregation [697]. It
23
attenuated tau hyperphosphorylation by inhibiting
GSK-3␤ [698].
Myrcetin is a naturally occurring regulator of metalinduced A␤ aggregation and neurotoxicity [699, 700].
Naringin showed memory enhancing activity in
mice [701].
NeurocentRX Pharma is investigating a natural
product-based compound for the treatment of cognitive
diseases (Thomson Reuters Pharma, update of February 17, 2012).
Nordihydroguaiaretic acid inhibited growth arising from direct A␤ protofibril association [599, 702,
703].
O4 (an orcein-related small molecule) was able to
convert toxic A␤ oligomers to nontoxic ␤-sheet-rich
amyloid fibrils [704].
Obovatol, a biphenolic compound isolated from
Magnolia obovata, attenuated scopolamine-induced
cognitive dysfunctions [705], improved cognitive
functions in animal models of AD [706], and
attenuated LPS-induced memory impairments in mice
via inhibition of NF-κB signaling pathway [707, 708].
Oleuropein and derivatives from olives were recognized as tau aggregation inhibitors [709].
Oren-gedoku-to exerts its potential use for the
treatment of AD as a weak, reversible inhibitor of
indoleamine-2,3-dioxygenase [710].
Oroxylin A is a flavonoid compound that is found in
the root of Scutellaria baicalensis Georgi. It attenuated
the memory impairment induced by transient bilateral
common carotid artery occlusion in mice [711].
1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose
is the active constituent of the traditional medicinal
herb Paeonia suffruticosa. It showed potent A␤
anti-aggregation effects in vitro and in vivo [712].
Piceatannol showed protective effects against A␤induced neuronal cell death [713].
Pinocembrin, a flavonoid abundant in propolis, protected against A␤-induced toxicity in neurons [714].
Polyphenol derivatives (Pharma Eight, Nagoya)
probably interacted with A␤ through ␲ – ␲ stacking
interactions via the aromatic amino acids of A␤ [715].
For a review, see [716] (Thomson Reuters Pharma,
update of January 13, 2011).
Procyanidins extracted from the lotus seedpod
reversed memory impairment in cognitively impaired
aged rats associated with decreased hippocampal
CREB phosphorylation [717, 718].
Prosopis cineraria (L.) Druce (Leguminosae), a
plant of the Thar Desert of India and Pakistan, is used
traditionally by local people for the treatment of memory disorders and to arrest wandering of the mind.
24
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
The extract exerted significant nootropic activity in the
Morris water maze test, which may be attributed to the
inhibition of brain acetylcholinesterase [719].
Puerarin, a phytoestrogen isolated from Pueraria
lobata, attenuated A␤-induced cognitive impairment
[720–723, 1712].
Quercetin-O-glucuronide significantly reduced the
generation of amyloid-␤ peptide [1713].
Pycnogenol protected neurons from A␤-induced
apoptosis [724].
Quercetin showed protective effects against A␤42
in primary neurons [586, 725]).
Rosmarinic acid protected PC12 cells from
A␤-induced neurotoxicity [599, 726]. Subchronic
administration of rosmarinic acid, a natural prolyl
oligopeptidase inhibitor, enhanced cognitive performance [727].
Rutin inhibited A␤ aggregation and cytotoxicity,
attenuated oxidative stress, and decreased the production of nitric oxide and proinflammatory cytokines
[728].
Saffron from Crocus sativus had an inhibitory effect
on A␤ aggregation [729, 730]. It was administered
to 46 patients with probable AD in a 16-week double blind study (15 mg twice a day). Saffron was safe
and effective [731]. A 22 week study corroborated the
first results [732]. Saffron may be a source of novel
acetylcholinesterase inhibitors [733].
Salidroside showed neuroprotective effects against
A␤-induced oxidative stress in SH-SY5Y human neuroblastoma cells [734].
S-allyl-L-cysteine, the main constituent of garlic,
protected against A␤-induced apoptosis and attenuated
caspase-3 activation, DNA fragmentation and PARP
cleavage [648]. It exerted protective effects on A␤induced cell death in NGF-differentiated PC12 cells
[735] and protected against A␤-induced neurotoxicity in organotypic hippocampal cultures [736]. For a
review on garlic extract and one of its active ingredients, S-allyl-L-cysteine, see [646].
Silibinin, a flavonoid derived from Silybum marianum, prevented memory impairment induced by
A␤25-35 in the Y-maze and novel object recognition
tests in mice [737].
Sinapic acid is a phenylpropanoid compound with
anti-inflammatory and neuroprotective effects in a
mouse model of A␤1-42 protein-induced AD [738].
Souvenaid (Nutricia, Châtel-St-Denis, Switzerland) is a mix of nutrients including the omega-3
fatty acid docosahexanoic acid, uridine monophosphate, and choline, dietary precursors for the synthesis
of phospholipids. Two clinical trials, Souvenir I, which
lasted 12 weeks, and Souvenir II, which lasted 24
weeks, were concluded [739–741].
Substance P, the tachykinin undecapeptide, protected cerebellar granule cells against A␤-induced
apoptosis [742].
Syringin from the dried stem barks of Fraxinus
rhynchophylla protected against A␤-induced toxicity
in neuronal cells [743].
Tannic acid destabilized A␤ fibrils in vitro [744,
745]. It is a natural ␤-secretase inhibitor [746].
␣-Tocopherol quinone inhibited A␤ aggregation
and cytotoxicity, disaggregated preformed fibrils and
decreased the production of ROS, nitric oxide, and
inflammatory cytokines [747].
Thymol showed cognitive-enhancing activity in two
rat models of dementia [580].
Total coptis alkaloids produced a protective effect
on A␤25-35 -induced learning and memory dysfunction
in rats [748].
Ursolic acid attenuated A␤-induced apoptosis in a
dose dependent manner [749].
Vitamin A has anti-oligomerization effects on A␤
in vitro [750].
Vitamin B12 deficieny is associated with cognitive
impairment [1714]. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily)
were effective in correcting biochemical defiency, but
improved cognition only in patients with pre-existing
vitamin B12 deficiency [1715].
Vitamin D defiency is associated with increased
odds of cognitive impairment [1716–1718].
Withania somnifera (also known as Ashwagandha,
an Indian ginseng) is a nootropic agent promoting
cognition including memory [751]). W. somnifera
administered once daily over 30 days reversed behavioral deficits, plaque pathology, accumulation of A␤
peptides and oligomers in the brains of middle-aged
and old A␤PP/PS1 AD mice. Enhanced expression of
low-density lipoprotein receptor-related protein (LRP)
in brain microvessels and the A␤ degrading protease
neprilysin occurred 14–21 days after a substantial
decrease in brain A␤ levels [752].
Wuzi Yanzong Granule improved memory functions in patients with MCI [753].
Yokukansan (TJ-54), a traditional Japanese herbal
medicine, was tested in clinics for potential antidementia effects [754]. Spatial memory in a rat model
of early AD was improved [755].
Zokumei-to (ZMT) attenuated A␤25-35 -induced
memory impairment [756].
The Central Drug Research Institute (India) was
developing bacosides A and B, which are saponin
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
nootropic agents. The compounds were in Phase II
clinical evaluation, but it appears that the development
was terminated. Also the development of CBNU06 (Chungbuk University), DCB-AD1 (Development
Center for Biotechnology), dysiherbaine (Daiichi
Suntory Biomedical Research Co., a compound isolated from the Micronesian sponge Dysidea herbacea
[757]), of the nordihydroguaiaretic acid derivative
EM-4232 (Eromos Pharmaceutical LLC), HSS808, HSS-818, HSS-838, HSS-848 and HSS-888
(HerbalScienceLLC Singapore; standardized turmeric
curcuma longa extracts), of LHM-123 (Mazal Plant
Pharmaceuticals), MDF-004 and MDF-005 (Neuron
BioPharma), and of YY-1224 and YY-1824 (Yuyu;
orally available terpene trilactones extracted from
Ginkgo biloba [758]) was terminated.
NOOTROPICS (“DRUGS WITHOUT
MECHANISM”)
In this chapter compounds are described, whose
mechanism(s) of action are unknown. Initiation of clinical trials was based on positive effects on impaired
brain functions in experimental animals after proof of
good tolerability.
LSL-001 (Laboratoire S. Lasnier, Etaules, France)
is a nootropic compound in Phase II clinical trials since
June 2011 for the potential treatment of AD (Thomson
Reuters Pharma, update of June 5, 2012). The structure
was not disclosed.
N-251 (Neurokos Inc., Palo Alto, CA) is a compound of an undisclosed mechanism of action for
the potential treatment of AD. Phase II clinical trials
started in May 2009 (Thomson Reuters Pharma, update
of January 16, 2012). The structure of N-251 was not
communicated.
PF-03049423 (Pfizer) is a neurorestorative compound for the potential treatment of neurological
disorders including stroke recovery. In December
2010, a randomized, double-blind, placebo-controlled
Phase II trial was initiated in the US and in South Korea
(n = 240) (Thomson Reuters Pharma, update of August
13, 2012). The structure was not communicated.
TPM-189 (Teikoku Pharma USA, San Jose, CA) is
a transdermal formulation of a small molecule therapeutic for the potential treatment of AD in Phase
II development (Thomson Reuters Pharma, update of
May 17, 2012). The structure was not communicated.
VI-1121 (VIVUS Inc., Mountain View, CA) is a
nootropic agent in Phase II clinical trials (n = 50) since
August 2011 in the US (NCT01428362) (Thomson
25
Reuters Pharma, update of September 9, 2011). The
structure of VI-1121 was not communicated.
ASP-0777 (Astellas Pharma) is in Phase I clinical trials since May 2009 (Thomson Reuters Pharma,
update of September 19, 2012). The structure was not
disclosed.
Lilly is developing a small molecule for the treatment of cognitive impairment in schizophrenia in
Phase I clinical trials since July 2012. (Thomson
Reuters Pharma, update of November 13, 2012). The
structure was not disclosed.
RO-5508887 (Roche) is a nootropic agent in
Phase I clinical trials in healthy male volunteers in
France since October 2011 (Thomson Reuters Pharma,
update of August 16, 2012). The structure was not
disclosed.
SEP-363856 (Sunovion Pharmaceuticals, Marlborough MA and Sumitomo Chemical) is an orally active
compound with novel mechanism of action for the
treatment of schizophrenia. The drug is in Phase I in the
US. (Thomson Reuters Pharma, update of November
5, 2012). The structure was not disclosed.
TAK-357 (Takeda) is a cognitive enhancer with
unspecified drug target in Phase I clinical development
(Thomson Reuters Pharma, update of July 30, 2012).
The structure was not communicated.
There are currently many nootropic agents in preclinical evaluation (in alphabetical order):
AC-0523 (Neuera, a subsidiary of Accera, Broomfield, CO) (Fig. 11) is indicated for the treatment
of mitochondrial dysfunction-related HD (Thomson
Reuters Pharma, update of February 15, 2012).
AFX-929 (Afecta Pharmaceuticals; Irvine, CA) is a
nootropic agent in preclinical development (Thomson
Reuters Pharma, update of November 10, 2011). The
structure was not disclosed.
Alzheimer’s disease therapeutics (Berg Pharma,
Nashville TN) are nootropic compounds for the potential treatment of AD (Thomson Reuters Pharma,
update of April 17, 2012). The structures were not
disclosed.
Alzheimer’s disease therapeutics (SienaBiotech/
Roche) are neuroprotectant compounds for the potential treatment of AD (Thomson Reuters Pharma,
update of February 8, 2012). The structures were not
disclosed.
Alzheimer’s disease therapy (Reyon Pharmaceuticals, Seoul) is a therapeutic program for the potential
treatment of AD (Thomson Reuters Pharma, update of
June 20, 2012). The structures were not disclosed.
AVN-457, AVN-458, and AVN-492 (Avineuro Pharmaceuticals, San Francisco, CA) are nootropic agents
26
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 11. Nootropics and one peptide.
in preclinical development (All three drugs in Thomson Reuters Pharma, update of August 19, 2011). The
structures were not disclosed.
CPC-001 (Chase Pharmaceuticals, Washington,
DC) is a compound for the palliative treatment of AD
(Thomson Reuters Pharma, update of July 12, 2012).
The structure was not communicated.
CWF-0804 (JW Pharmaceutical Corp., Choongwae
Holdings, Seoul) is a nootropic agent in development for the Korean and Japanese markets (Thomson
Reuters Pharma, update of May 11, 2012). The structure was not disclosed.
D-130 (Envoy Therapeutics, Jupiter, FL) is a compound targeting the cortex region of the brain using
bacTRAP technology for the potential treatment of
cognition deficits (Thomson Reuters Pharma, update
of June 1, 2012). The structure was not disclosed.
D-180 (Envoy Therapeutics, Jupiter, FL) is a compound targeting the striatum region of the brain using
bacTRAP technology for the potential oral treatment
of PD (Thomson Reuters Pharma, update of September
12, 2012). The structure was not disclosed.
GSK-2647544 (GSK) is a neuroprotectant for the
potential treatment of Alzheimer’s disease. In October
2012, a single-blind, randomized, placebo-controlled,
Phase I trial was expected to begin later that month in
Australia in healthy male subjects (expected n = 16). At
that time, the trial was expected to complete in April
2013 (Thomson Reuters Pharma, update of November
20, 2012). The structure was not disclosed.
J-147 (Salk Institute for Biological Studies)
(Fig. 11) is a drug that improved memory in normal
rodents and prevented cognitive decline in transgenic
mice of AD (Thomson Reuters Pharma, update of
December 22, 2011).
JAY 2-22-33 (Medical College of Georgia) (Fig. 11)
significantly reduced A␤ toxicity and improved cognitive performances in transgenic AD mice [759].
JWB1-84-1 (Medical College of Georgia) (Fig. 11)
is a tertiary amine analogue of choline from the laboratory of the late Prof. Jerry J. Buccafusco. It produced a
dose-dependent decrease in the number of errors made
by well-trained AD-transgenic mice in the radial arm
water maze test [759, 760].
KD-901 (Kwang Dong Pharmaceutical Co., Seoul)
is a nootropic drug in preclinical evaluation (Thomson Reuters Pharma, update of March 1, 2011). The
structure was not disclosed.
KU-046 (Kareus Therapeutics and Connexios Life
Sciences, Atlanta, GA) is a combination drug, which
demonstrated significant improvement of cognition
(Thomson Reuters Pharma, update of May 29, 2012).
The structure was not disclosed.
LNK-3186 and LNK-3248 (AstraZeneca after its
acquisition of Link Medicine Corp., Waltham, MA)
are nootropic compounds (For both Thomson Reuters
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Pharma, update of July 13, 2012). The structures were
not disclosed.
Maltoyl p-coumarate attenuated cognitive deficits
in rats treated with scopolamine or with A␤42 [761].
MeN061016-1 (Lijun International Pharmaceutical, Hong Kong) is a small molecule neuroprotectant
(Thomson Reuters Pharma, update of June 26, 2012).
The structure was not disclosed.
MPP-26 (M et P Pharma, formerly Mattern Pharmaceuticals, Emmetten, Switzerland) is an intranasal gel
formulation of pregnenolone for the potential enhancement of memory (Thomson Reuters Pharma, update of
January 27, 2012).
NNZ-2591 (Neuren Pharmaceuticals, Auckland,
NZ) (Fig. 11) is an orally active neuroprotectant diketopiperazine derivative for the treatment of brain injury
and PD [762] (Thomson Reuters Pharma, update of
August 31, 2012).
NXD-9062 (Nymox Pharmaceutical Corp., Quebec)
is a neuroprotectant for the potential treatment of AD
(Thomson Reuters Pharma, update of February 22,
2012). The structure was not disclosed.
NXT-182 (Inception Sciences Inc., San Diego) is
a novel small molecule neuroprotectant for the potential treatment of CNS disorders, including Alzheimer’s
disease, Parkinson’s disease and age-related cognitive
decline (Thomson Reuters Pharma, update of October
29, 2012). The structure was not disclosed.
OG-635 (Oryzon Genomics, Barcelona) is a
nootropic agent for the potential treatment of AD and
PD (Thomson Reuters Pharma, update of May 31,
2012). The structure was not disclosed.
Pentylenetetrazole (Balance Therapeutics, Hillsborough, CA) is investigated for the potential treatment
of cognitive impairment in Down’s syndrome (Thomson Reuters Pharma, update of September 4, 2012).
PNB-03, PNB-04, and PNB-05 (PharmaNeuroBoost NV, Limburg, Belgium) are nootropic agents for
the potential treatment of PD (PNB-03), AD (PNB-04),
and obsessive compulsive disorders (PNB-05) (Thomson Reuters Pharma, update of February 1, 2012). The
structures were not communicated.
PTI-125 (Pain Therapeutics Inc., Austin, TX)
reduced A␤-related AD pathogenesis by targeting filamin A [763] (Thomson Reuters Pharma, update of
August 3, 2012). The structure was not communicated.
RP-4000 (Reviva Pharmaceuticals, San Jose, CA)
is a small molecule nootropic agent (Thomson Reuters
Pharma, update of December 27, 2011). The structure
was not communicated.
SEL-103 (Selvita Life Sciences Solutions, Krakow,
Poland and Orion, Espoo, FL) is a program inves-
27
tigating small molecule nootropic agents (Thomson
Reuters Pharma, update of July 4, 2012). Structures
were not communicated.
SKL-A4R (SK Biopharmaceuticals, formerly SK
Life Science, Fair Lawn, NJ) is a small molecule
nootropic agent (Thomson Reuters Pharma, update of
March 19, 2012). The structure was not communicated.
TYP-1 (NOBEL ILAC, Istanbul, Turkey) is a small
molecule neuroprotectant (Thomson Reuters Pharma,
update of July 30, 2011). The structure was not communicated.
The development of ABIO-08-01 (BTG-1640;
Abiogen under license from British Technology
Group, BTG), ADS-8703 (Adamas Pharmaceuticals),
AIP-002 (American Home Products, Wyeth, now
Pfizer), AIT-034 (Spectrum Pharmaceuticals, formerly
NeoTherapeutics), Alzheimer’s disease therapeutics
(DuPont/Scios), ALE-26015 (Allelix Pharm-Eco LP),
aloracetam (Hoechst, now sanofi), Alzene (Bar Ilan
University and Ivax); AQW-051 (Novartis; Phase II
trials for treatment of schizophrenia and PD are ongoing), ASP-2535 and ASP-2905 (Astellas), AVN-397
(Avineuro Pharmaceuticals; in Phase II trials for the
treatment of anxiety), AWD-52-39 (Alzneimittelwerke Dresden, elbion), AZD-2858 (AstraZeneca),
BCE-001 (4-chloro-phenoxy-acetic acid-1,3-bis
(dimethylamino)-2-propylester [764–766]), BD-1054
(Russian Academy of Medical Science), BGC-200406 (RS-0406; SEN-1269 [767]; Senexis under
license from BTG under license from Sankyo), BGC20-0466 (BTG), BGC-20-1178 (Senexis under license
from BTG under license from Sankyo), BGC-20-1259
(BTG under license from Sankyo), BMS-181168
(BMY-21502; Bristol-Myers Squibb [768–770]),
BTG-4247 (BTG), BW-394-U (GSK), CG-301338
(CrystalGenomics), CL-287663 (KE-748; Lederle
Laboratories, now Pfizer), of CLL-502 (CLL Pharma),
CM-2433 (Cenomed, a subsidiary of Abraxis BioScience in collaboration with Medical College of
Georgia), CX-417, CX-423 and CX-438 (Cortex
Pharmaceuticals), DW-514 and DW-0811 (Daewon
Pharm), DWJ-209 (Daewoong Pharmaceutical Co.),
of the coumarin derivative ensaculin (KA-672;
Dr. Willmar Schwabe [771–777]), ETX-6765 (eTherapeutics), F-94517 (Pierre Fabre), gedocarnil
(Bayer Schering Pharma), GM-1416 (GliaMed Inc.),
GT-4035 and GT-4054 (Gliatech), HL-026 (HanAll
Biopharma), HMR-2420 (Hoechst Marion Roussel,
now sanofi), HSB-13 (EncephRx, a spin-out of the
Southern Methodist University and the University of
Texas [1719]), HTC-867 (Wyeth, now Pfizer), IQ200
and IQ-201 (Immune Network under license from
28
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
the University of British Columbia), JNJ-39393406
(Janssen Pharmaceutica), LX-104 (Laxdale, Amarin
Corp.), of the MBARC program (EnVivo Pharmaceuticals), MK-0249 (Merck & Co), MK-5757
(Merck & Co), MG-19649 (Molecular Geriatrics,
now Applied Neuro Solutions), MP-100 (Addiction
Therapeutix), MR-708 (Medea Research), NDD-094
(Novartis [778]), NeoEA-1001 (neoCodex), nooglutil
(Russian Academy of Medical Sciences [779]), NSA789 (Wyeth, now Pfizer), OF-5858 and OF-6145 (All
Russian Research Institute of Pharmaceutical Chemistry), Oligotropin (HF-0420; Loyola University of
Chicago), Org-31433 (Organon Biosciences, now
MSD OSS BV), PF-05297909 (Pfizer), Prisotinol
(CGS-5649B; Ciba-Geigy, Novartis [780–783]), procaine hydrochloride (Samaritan Pharmaceuticals),
PRX-4001 and PRX-4006 (Proximagen), R-641 and
Ro-40-1641 (both Roche), RU-47067 and RU-52583
(Roussel-Uclaf, now sanofi), sabeluzole (Janssen
Pharmaceutica NV, Johnson & Johnson [784–789]),
SCH-54388 (Schering-Plough, now Merck; a metabolite of felbamate), sibopirdine (EXP921; Du Pont
Merck [790]), silicon-containing pyridylsubstituted
isoxazoles (Latvian Institute of Organic Synthesis),
SLV-351 (Solvay Pharmaceuticals, now Abbott
Laboratories), SN-104 (Sention), SNK-882 (Sanwa
Kagaku Kenkyusho), SPPI-339 (SPI-339, NEO-339;
Spectrum Pharmaceuticals, formerly NeoTherapeutics), SRA-997 (Novartis), ST-587 (Boehringer
Ingelheim), T-9021 and T-9022 (QRxPharma), TAK065 (Takeda), tenilsetam (Hoechst Marion Roussel,
now sanofi [791, 792]) trifusal (Grupo Uriach),
V-0191 (Pierre Fabre) and of Z-4105 (Zambon) was
terminated.
PEPTIDES
Cerebrolysin (Ebewe Pharmaceuticals, Vienna,
Austria, launched, available in 1 ml, 5 ml, and 10 ml
ampoules and in vials of 30 ml and 50 ml for intramuscular or intravenous injection or intravenous infusion)
is “derived through a biotechnological procedure from
highly purified porcine brain proteins and is comprised of free amino acids and biologically active,
short chain peptides” [793]. Cerebrolysin acted as
a presynaptic GABAB receptor agonist [794]. The
nootropic effects of cerebrolysin were investigated in
depth [795–799]. Cerebrolysin protected neurons from
ischemia-induced loss of microtubule-associated protein 2 [800]. Effects of cerebrolysin on A␤ deposition
in transgenic mice were studied extensively [801–807].
The pharmacology of neurotrophic treatment with
cerebrolysin was reviewed [808]. Clinical data were
published (in chronological order) [793, 809–823].
First clinical results of a combination treatment of cerebrolysin and donepezil were reported [824]. Data of
cerebrolysin in AD were compiled [825]. The safety
profile of cerebrolysin in dementia and stroke trials was
described [826].
Cortexin (Geropharm, St. Peterburg, Russia)
is a launched polypeptide with neuroprotective,
nootropic and antioxidant properties, for the intramuscular treatment of central nervous system injury
caused by cerebrovascular accidents, encephalitis,
encephalopathies, epilepsy and trauma (Thomson
Reuters Pharma, update of October 05, 2012). The
structure was not communicated.
Davunetide (intranasal, AL-108, NAP, Allon Therapeutics, Vancouver) is an 8-amino acid peptide
(NAPVSIPQ) derived from the activity-dependent
neuroprotective protein. A Phase III clinical trial was
initiated for the treatment of patients with progressive supranuclear palsy in December 2010. A Phase
II clinical trial in AD patients started in January 2007
(Thomson Reuters Pharma, update of July 17, 2012).
Allon Therapeutics is also developing injectable intravenous and subcutaneous formulations of davunetide.
There are numerous publications on the extensive
preclinical characterization of davunetide describing protection of the brain against ischemic injury
in rats [827], inhibition of the aggregation of A␤
[828], decrease of anxiety-like behavior in aging mice
[829], reduction of the severity of traumatic head
injury [830], reduction of accumulation of A␤ and
of tau hyperphosphorylation [831–833], stimulation
of microtubule assembly [834, 835], enhancement
of cognitive behavior in transgenic mice [836]),
and improvement in motor function and reduction
of ␣-synuclein inclusions in mice overexpressing
␣-synuclein [837]. Reviews on davunetide were
published [838–847]. The effects of davunetide on cognition and functional capacity in schizophrenia were
described [848] (Thomson Reuters Pharma, update of
September 21, 2012).
AM-111 (XG-102, D-JNKI-1; Auris Medical and
Xigen, a spin off from the Centre Hospitalier Universitaire Vaudois and the University of Lausanne) is
an injectable protease-resistant peptidic derivative of
the JNK-inhibiting protein IB-1 for the i.v. treatment
of acute sensorineural hearing loss, stroke, and AD
[849–852]. A Phase IIb trial for acute sensorineural
hearing loss was initiated in January 2009 (n = 210) and
results are expected in autumn of 2012. Auris Medical
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
is also investigating a topical gel formulation of AM111 (Thomson Reuters Pharma, update of August 31,
2012).
Etanercept (ENBREL, NK-001; Neurokine Pharmaceuticals, Vancouver) is a recombinant fusion
protein of 934 amino acids (mol. weight: 150 kDa)
composed of a dimer of the extracellular portion of
human TNFR-2 fused to the Fc fragment of human
IgG1 [853, 854]. A rapid cognitive improvement
following perispinal etanercept administration to 15
probable-AD patients treated once weekly for 6 months
was reported [855–857]. See also the commentary
[858]. In December 2010, the drug was in Phase II
development for the potential treatment of neurocognitive impairment following coronary artery bypass graft
surgery (Thomson Reuters Pharma, update of July 9,
2012).
FGL (ENKAM Pharmaceuticals, Copenhagen,
Denmark) is a peptide neural cell adhesion molecule
mimetic for the potential treatment of AD and stroke.
In December 2011, clinical studies including three
Phase I studies, one proof-of-concept Phase IIa study
in AD, and a pilot study in patients recovering from
stroke was planned to begin in 2012 (Thomson Reuters
Pharma, update of April 23, 2012). Enkam was previously developing FGLL, a peptide neural cell adhesion
molecule mimetic, for the potential intranasal treatment of AD and stroke. In May 2005, the drug was
shown to be safe and well tolerated in a Phase I study
for AD. By December 2011, the drug was no longer
being developed due to the lack of flexibility for the
route of administration.
Glypromate (Gly-Pro-Glu) is naturally cleaved
from the N-terminal sequence of IGF-I and displayed
neuroprotective actions in vitro and in vivo [859–861].
It protected against A␤-induced somatostatin depletion
in rat cortex [862, 863].
NNZ-2566 (Neuren Pharmaceuticals, Auckland,
NZ) (Fig. 11) is an analogue of glypromate with
an additional ␣-methyl-group on the proline moiety,
which resulted in an improved half-life and better
oral bioavailability. In March 2012, a randomized,
double-blind, placebo-controlled Phase I study was
initiated in healthy volunteers (n = 32) in Australia.
Potential indications are mild traumatic brain injury,
Rett syndrome, PD, and AD [864– 867]. Excellent synthetic organic chemistry was described [868–871]. In
November 2012 the IND was filed for a Phase II trial.
At that time an application was submitted to the Texas
Children’s Hospital IRB and enrollment was expected
to begin pending approval by the FDA and the Texas
Children’s Hospital IRB. (Thomson Reuters Pharma,
29
update of November 23, 2012). (Thomson Reuters
Pharma, update of August 31, 2012). Neuren is also
developing a formulation for intravenous infusion.
There are many peptides in preclinical evaluation for
the potential treatment of AD (in alphabetical order):
AL-408 (Allon Therapeutics, Vancouver) is the
orally active D-amino acid derivative of davunetide (AL-108) and an active element of the PARP-1
activating activity-dependent neuroprotective protein
(Thomson Reuters Pharma, update of November 9,
2011).
Alzimag (IMAGENIUM, Paris, France) is a peptide
for the potential treatment of AD (Thomson Reuters
Pharma, update of December 22, 2011). The structure
of the compound were not communicated.
C3bot peptides (Charité Medical School Berlin and
Hannover Medical School) are short neuron-specific
neuritogenic peptides derived from the C3 exoenzyme
of Clostridium botulinum, which transiently activated
RhoA for the potential treatment of neurodegenerative disorders including AD, PD, Huntington’s chorea,
spinal cord and traumatic brain injury [872–875]
(Thomson Reuters Pharma, update of June 7, 2012).
COG-112, COG-133, and COG-1410 (Cognosci
Inc., Research Triangle Park, NC) are apoE-mimetic
peptides that showed consistent reduction of both A␤
deposition and of tau hyperphosphorylation in three tau
transgenic mouse models and in two A␤PP transgenic
mouse models [876, 877] (Thomson Reuters Pharma,
update of June 5, 2012 for COG-112 and of September
11, 2012 for COG-133 and COG-1410).
G-79 (BN-201; Bionure, Barcelona) is a peptide for
the potential treatment of multiple sclerosis, ALS, AD,
PD, and glaucoma (Thomson Reuters Pharma, update
of July 4, 2012).
KIBRA pathway modulators (Amnestix Inc., a
wholly owned subsidiary of SYGNIS Pharma; Heidelberg, Germany) offer a new genetic link to cognition
that may benefit patients suffering from AD. For the
association of KIBRA and late onset AD, see [878];
for enhancement of cognition in anxiety disorders
[879] (Thomson Reuters Pharma, update of August
14, 2012).
Leptin reduced the accumulation of A␤ and phosphorylated tau in rabbit organotypic slices [880–882].
The company Neurotez (Bridgewater, NJ) is investigating leptin as an A␤ synthesis inhibitor for the
potential treatment of AD. The company planned to
file an IND in 2012. Effects of leptin on memory
processing were described [883–885]. Leptin induced
proliferation of neuronal progenitor cells [886] (Thomson Reuters Pharma, update of August 24, 2012).
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
MT-007 (MT-007-LRPIV; recombinant LRP fragments; Socratech LLC, Rochester NY) is produced by
stable transfected baby hamster kidney cells expressing LRP-IV. The preparation improved cerebral blood
flow, learning and memory in a mouse model of AD
(Thomson Reuters Pharma, update of April 23, 2012).
Netrin-1 (BioMarin Pharmaceuticals, Novato, CA,
under license from the Buck Institute) interacted with
A␤PP and regulated A␤ production [887, 888]. Netrin1 increased soluble A␤PP␣ and decreased A␤1-40
and A␤1-42 levels in a J20 mouse model of AD.
An intranasal delivery is planned (Thomson Reuters
Pharma, update of July 20, 2012).
NNZ-4921 and NNZ-4945 (NRP-2945, an 11-mer;
CuroNZ under license from Neuren Pharmaceuticals,
Auckland, NZ) are neuronal regeneration peptides for
the potential treatment of multiple sclerosis and motor
neuron disease, respectively [889] (Thomson Reuters
Pharma, updates of June 18, 2012 and September 7,
2012, respectively).
NRG-101 (Mind-NRG, Geneva, Switzerland under
license from ProteoSys, Mainz, Germany) is an
injectable neuregulin peptide for the potential treatment of PD, AD, and schizophrenia (Thomson Reuters
Pharma, update of July 6, 2012).
NT-1 and NT-2 (Neurotez, Bridgewater, NJ) are
small peptides, which block the interaction between
mutant presenilin and cytoplasmic linker protein 170
(CLIP-170) that is linked to increased A␤ levels (Both
Thomson Reuters Pharma, update of June 6, 2012).
NX-210 (Neuronax, Saint Beauzire, France) is the
lead compound of a series of peptides for the potential
treatment of spinal cord injury and other neurological
disorders, such as stroke, AD, PD, and traumatic brain
injury (Thomson Reuters Pharma, update of June 29,
2012). The structure was not communicated.
Pepticlere (DP-68 and DP-74; ProteoTech, Kirkland, WA) is the name of small molecule nasal sprays,
6- to 9-mer peptides that inhibit A␤ fibril formation (Thomson Reuters Pharma, update of August 22,
2012). The structures were not disclosed.
PP-0301 (Hybio Pharmaceutical, Guangdong,
China) is a polypeptide for the potential treatment AD
(Thomson Reuters Pharma, update of September 20,
2011).
RAP-310 (Rapid Pharmaceuticals, Zug, Switzerland) is a small stabilized receptor active peptide
targeting the CCR5 receptor for the potential treatment
of AD (Thomson Reuters Pharma, update of October
1, 2012). The structure was not communicated.
RG-01, RG-09, and RG-018 (ReGen Therapeutics,
London) are neuroprotectant peptides from colostrinin
(vide infra) for the potential treatment of neurodegenerative diseases including AD (Thomson Reuters
Pharma, update of June 27, 2012). The structures were
not communicated.
SX-AZD1 (Serometrix, Pittsford, NY) is a peptide
mimetic interacting with APOE4 (Thomson Reuters
Pharma, update of July 29, 2011). The structure was
not communicated.
XD4 is a heptapeptide isolated from a Ph.D.-C7
library through phage display that rescued memory
deficits in AD transgenic mice by significantly inhibiting A␤42 -induced cytotoxicity, increasing microglial
phagocytosis of A␤, and decreasing A␤-induced generation of ROS and nitric oxide [890].
Colostrinin (ReGen Therapeutics, London) is a
polypeptide complex isolated from ovine colostrum
containing a high proportion of proline (25%) and
hydrophobic amino acids (40%). It is composed of
peptides of molecular mass up to 3,000 Da. It reduced
aggregation of A␤ [891, 892] and alleviated A␤induced toxicity [893]. It facilitated learning and
memory in rats [894] and chicks [895]. Effects on gene
expression were described [896]. Clinical results were
presented (in chronological order) [897–901]. Reviews
on colostrinin were published [902, 903].
The development of colostrinin for the treatment
of AD patients was discontinued. The compound was
launched as a nutraceutical in Australia in July 2007
(Thomson Reuters Pharma, update of May 17, 2011).
The development of ANA-1 and ANA-5 (Alzhyme
Pty; phage peptides, which bind to A␤ to inhibit its generation of hydrogen peroxide [904]), adrenomedullin
peptides (National Institutes of Health), AS-602704
(Merck Serono under license from Axonyx), C-AVP(4-9) (Yakult Central Institute for Microbiological
Research), ebiratide (Hoe-427; Hoechst, now sanofi;
an ACTH (6-9) derivative [905–907]), gilatide
(a nonapeptide of Axonyx under license from
Thomas Jefferson University), metallothionein (Neurosciences Victoria and the University of Tasmania
[908, 909]) and of noopept (GVS-111, SGS-111;
DVD-111; Saegis Pharmaceuticals under license from
the Russian Academy of Sciences; a nootropic
dipeptide analogue of piracetam [910–920]) was
terminated. The development of NC-1900 (Nippon Chemiphar, the active fragment analog of
arginine vasopressin [921–925]), PR-21C (Pharmaxon; a polysialylated form of the neural cell
adhesion molecule) and of RGX-100 and RGX200 (RemeGenix Inc., Cortica Neuroscience; A␤
production-inhibiting BRI2-derived peptides for the
intranasal administration to AD patients [926–933])
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
was discontinued. The development of SEM-606 (University of Manchester) and of TKP-1001 (EUSA
Pharma, formerly Tasliker under license from The
Open University) was terminated.
DRUGS PREVENTING AMYLOID-␤
AGGREGATION
Plasma A␤ levels can be linked directly to specific cognitive changes that constitute the conversion
from MCI to AD [934–939]. The relationship between
atrophy and A␤ deposition in AD was investigated
thoroughly [940–942]. A review of the literature correlating Alzheimer disease neuropathologic changes
with cognitive status was provided [947]. The molecular and neurophysiological mechanisms of amyloid-␤
and cognition in Alzheimer’s disease were outlined
[1720]. A rapid decline of memory in healthy older
adults with high amyloid-␤ load was described [1721],
which was more important than ApoE genotype
[1722]. Cognitive decline in adults with high amyloid␤ load was evaluated [1723]. A␤ assemblies mediated
rapid disruption of synaptic plasticity and memory
[943]. The topic “A␤ toxicity in Alzheimer’s disease”
was reviewed [944, 945]. A critical review on the amyloid cascade hypothesis was published [946]. Although
A␤ plaques may play a key role in AD pathogenesis,
the severity of cognitive impairment correlates best
with the burden of neurofibrillary tangles [947]. The
key interactions of apolipoprotein E and A␤ pathology
were reviewed [948].
The inhibition and reversion of A␤ misfolding and
aggregation is an approach, which has been followed
up by many research groups during years. Excellent
reviews dealing with this subject were published (in
chronological order) 1996: [949], 1998: [950, 951],
1999: [952–956], 2001: [957], 2002: [958–960], 2005:
[961, 962], 2006: [963], 2007: [964, 965], 2009: [495,
966–968], 2010: [969–971], 2011: [972, 973], 2012:
[974–976].
Tafamidis (PF-06291826, Fx-1006, Vyndaquel,
Pfizer following its acquisition of FoldRx Pharmaceuticals under license from the Scripps Research
Institute) (Fig. 12) is small-molecule transthyretin stabilizer for the oral treatment of transthyretin familial
amyloid polyneuropathy [977–980]. The drug was
approved by EMA in November 2011 was launched
in Europe in March 2012 [1724]. In June 2012, the
FDA issued a complete response letter and requested
the completion of a second efficacy study. For the identification of A␤ binding sites on transthyretin see [981];
31
for transthyretin amyloidosis see [982, 983] (Thomson
Reuters Pharma, update of September 25, 2012).
Eprodisate (1,3-propanedisulfonate disodium salt;
NC-503, Fibrillex, Kiacta; Celtic Therapeutics, St.
Thomas VI under license from Bellus Health) (Fig. 12)
is an orally active sulfated glycosaminoglycan mimetic
designed to inhibit the formation and deposition of
amyloid fibrils. A Phase III study was initiated in
December 2010 for the treatment of renal disease in
patients with AA amyloidosis [984–987] (Thomson
Reuters Pharma, update of September 5, 2012).
For ARC-029 (Archer Pharmaceuticals, Roskamp
Institute, Sarasota, FL; Phase III clinical trials),
see Chapter 7, Drugs interacting with Ion Channels
(=
/ Receptors).
For Davunetide (intranasal of via i.v. or s.c administration; Allon Therapeutics, Vancouver, Phase III
clinical trials), see Chapter 15, Peptides.
For APH-0703 (Aphios Corp., Woburn MA), a
nanoparticle formulation of APPH-9601 in Phase II
clinical trials since May 2010 (Thomson Reuters
Pharma, update of July 5, 2012), see Part 2, Chapter
2.35, Drugs interacting with Protein Kinase C.
Doxycycline hyclate (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) is in a Phase II study
(NCT01171859) in patients with transthyretin amyloidosis (n = 40) since July 2010. At oral doses of
200 mg for three months, doxycycline produced a
significantly lower decline in the ADAScog scores in
101 mild-to-moderate AD patients [988] (Thomson
Reuters Pharma, update of April 27, 2012).
ELND-005 (AZD-103; scyllo-inositol; scyllocyclohexanehexol, Elan, Dublin, Ireland, and Ellipsis
Neurotherapeutics, formerly Transition Therapeutics,
Toronto, Canada) (Fig. 12) is an orally available
inhibitor of A␤ peptide aggregation. Results of a Phase
II dose-ranging, randomized, placebo-controlled study
in 351 patients with mild-to-moderate AD treated for
78 weeks with either 250, 1,000, or 2,000 mg/day were
reported. Patients with mild AD receiving 250 mg of
ELND-005 had higher scores on the Neuropsychological Test Battery compared with placebo, which
were significant. In contrast ADCS-ADL scores were
not significant. The two higher doses were discontinued [989]. In August 2012, a Phase II study
was initiated in bipolar disorder patients in the US.
The study is expected to be completed in August
2014 (Thomson Reuters Pharma, update of September
14, 2012).
The endogenous brain inositols stabilized small
aggregates of A␤, which are non-toxic to NGFdifferentiated PC-12 cells and primary human neuronal
32
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 12. Drugs interacting with amyloid-␤.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
cultures [990]. In particular scyllo-inositol, when
given orally to transgenic mice, reversed AD phenotype, improved impaired cognition, and altered
cerebral A␤ pathology [991, 992]. Scyllo-inositol
dose-dependently rescued long-term potentiation in
mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human A␤ [993, 994].
Elevated scyllo-inositol concentrations were found in
patients with AD [995].
Syntheses of scyllo-inositol derivatives have been
reported [996]. The synthesis of the PET ligand [18 F]1-deoxy-1-fluoro-scyllo-inositol was described [997].
A comparison of three amyloid assembly inhibitors,
scyllo inositol, epigallocatechin gallate and the molecular tweezer CLR01 (vide infra) was published
[998].
SOM-0226 (SOM Biotech SL, Barcelona) is a drug
for the potential treatment of transthyretin amyloidosis in Phase II clinical development (Thomson Reuters
Pharma, update of May 30, 2012). The structure was
not communicated.
For AAD-2004 (GNT Pharma, Suwon, South
Korea) in Phase I clinical trials (Thomson Reuters
Pharma, update of May 4, 2012). See Part 2, Chapter 2.34. Drugs interacting with Prostaglandin D & E
Synthases, Part 2, Fig. 22.
Beta amyloid modulator (Medipost, Seoul) is in
Phase I clinical trials in South Korea since September 2011 for the potential treatment of AD (Thomson
Reuters Pharma, update of May 7, 2012). The structure
was not communicated.
BLU-8499 (formerly NRM-8499; Bellus Health,
formerly Neurochem, Quebec) is a prodrug of
tramiprosate (vide infra). It was evaluated in a singlecenter, randomized, double-blind, placebo-controlled
Phase I study in 84 young and elderly healthy subjects
to assess safety, tolerability and pharmacokinetics,
which started in March 2010. The data were reported
in January 2011. It showed improved gastrointestinal tolerability and lower inter-individual variability
of drug exposure compared to comparable doses of
tramiposate (Thomson Reuters Pharma, update of
September 5, 2012).
DWP-09031 (presumed to be DWJ-301; Daewong
Pharmaceutical Co. in collaboration with Medifron,
both South Korea) inhibited the production and aggregation of A␤. By January 2012, the Korean FDA
had approved an IND for a Phase I trial. The
randomized, double-blind, placebo-controlled study
(NCT01522586) is planned in healthy male volunteers (n = 64) to assess the safety, pharmacokinetics and
pharmacodynamics of DWP-09031 (Thomson Reuters
33
Pharma, update of July 27, 2012). The structure was
not disclosed.
For Exebryl-1 (ProteoTech, Kirkland, WA and
China licensee Tasly Pharmaceuticals; in Phase I clinical trials), see Chapter 13, Natural Products.
For NP-61 (NP-0361; Noscira, previously Neuropharma, Madrid; Phase I clinical trials; Thomson
Reuters Pharma, update of May 10, 2012), see Part
2, Chapter 2.1.1.2., Dual acetylcholinesterase and A␤
inhibitors.
Systebryl (ProteoTech, Kirkland, WA) is the lead
of a series of small molecules including PTI-19 and
PTI-51 for the potential treatment of systemic AA amyloidosis. In December 2011, Systebryl was in Phase I
studies (Thomson Reuters Pharma, update of December 21, 2011). Structures were not communicated.
There are many A␤ aggregation inhibitors in preclinical evaluation (in alphabetical order):
Alzheimer’s disease therapeutics (BioChromix
Pharma AB, Solna, Sweden) are compounds, which
achieved a significant reduction in plaque load and
neurotoxic A␤ aggregates. (Thomson Reuters Pharma,
update of August 24, 2012). The structures were not
communicated.
A␤ oligomer cellular prion protein binding
inhibitors (AstraZeneca under a sublicense from Axerion Therapeutics under license from Yale University)
are interacting with the cellular prion protein, the
high affinity receptor for A␤ oligomers [999–1003]
(Thomson Reuters Pharma, update of August 17,
2012). No structures were disclosed.
A␤ protein inhibitors (Neuropore Therapies, San
Diego CA) are peptidomimetic compounds that interfere with A␤ aggregates (Thomson Reuters Pharma,
update of July 16, 2012). Structures were not communicated.
A␤/tau protein aggregation inhibitors (CNRS,
FIST SA, Paris, France) are investigated for the potential treatment of AD (Thomson Reuters Pharma, update
of August 24, 2012). Structures were not communicated.
Amyloid-derived diffusible ligands are investigated by Merz Frankfurt, Germany under license from
Acumen Pharmaceuticals (Thomson Reuters Pharma,
update of June 12, 2012). The structures of the compounds were not communicated.
ARN-4261 (New York University and Aria Neurosciences, Hamden CT) (Fig. 12) and ARN-2966
(Fig. 12) are inhibitors of A␤ aggregation. ARN-2966
reduced A␤ deposition and memory deficit in transgenic mice. Following treatment a significant 25%
reduction in A␤ plaque load was noted compared with
34
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
mice that received a vehicle control. The data demonstrated that ARN-2966 was biostable and well tolerated
in transgenic mice with blood-brain barrier penetration after both oral and intravenous dosing (Thomson
Reuters Pharma, update of August 28, 2012).
AVCRI-104P4 (University of Barcelona) (Fig. 12)
inhibited A␤ aggregation including acetylcholinesterase- and self-induced-A␤ aggregation, ␤-secretase,
acetylcholinesterase, and butyrylcholinesterase (Thomson Reuters Pharma, update of September 28, 2012).
AVN-457, AVN-458 and AVN-492 (Avineuro Pharmaceuticals, San Francisco) are nootropic agents for
the potential treatment of cognitive disorders (Thomson Reuters Pharma, update of October 22, 2012). The
structures were not disclosed.
AZP-2006 (AlzProtect, Loos, France in collaboration with INSERM and the University of Lille II) is an
A␤PP modulator of undisclosed structure (Thomson
Reuters Pharma, update of July 4, 2012).
Beta-amyloid aggregation inhibitors (Medisyn
Technologies, Minnetonka, MN / Mount Sinai School
of Medicine) demonstrated significant A␤-lowering
and anti-aggregation activity in vitro. Two compounds
also reduced the amount of A␤ in mouse brain in vivo
(Thomson Reuters Pharma, update of June 21, 2012).
Structures were not communicated.
Beta-amyloid/alpha-synuclein/tau aggregation
inhibitors (Snowdon Inc., Vancouver) are expected
to enter Phase I trials in 2012 (Thomson Reuters
Pharma, update of August 19, 2011). The structures
of the compounds were not communicated.
Beta amyloid beta sheet formation inhibitors (AC
Immune, Lausanne, Switzerland) are small molecules,
which inhibited the aggregation of A␤ to oligomeric
and fibrillar species for the potential treatment of AD
and glaucoma [1004]. Two 3-aminopyrazole moieties
carrying additional aryl substituents were connected
via a linker. The concept of 3-aminopyrazoles with a
donor-acceptor-donor hydrogen bond pattern complimentary to that of the ␤-sheet of A␤42 was first investigated by Schrader and colleagues [1005–1013] (Thomson Reuters Pharma, update of September 24, 2012).
Beta-amyloid inhibitor (Icogenex, Seattle, WA) is
a small molecule therapeutic that normalizes the production of A␤ (Thomson Reuters Pharma, update of
June 26, 2012). The structure was not disclosed.
Beta-amyloid inhibitor (Star Scientific, Glen Allen
VI through its subsidiary Rock Creek Pharmaceuticals
in collaboration with the Roskamp Institute) reduced
A␤ when applied to cells (Thomson Reuters Pharma,
update of January 3, 2012). The structure was not
disclosed.
Beta-amyloid modulators (Crossbeta Biosciences,
Utrecht, The Netherlands) are small molecules, which
target A␤ oligomers and misfolded proteins (Thomson
Reuters Pharma, update of August 24, 2012). Structures were not communicated.
Beta-amyloid precursor protein modulators
(Alzcor Pharmaceuticals, Arlington, MA) are investigated for the potential treatment of AD (Thomson
Reuters Pharma, update of July 27, 2011). Structures
were not disclosed.
BMS-869780 (Bristol-Myers Squibb) (Fig. 12)
reduced A␤42 levels in transgenic mice at oral doses
and displayed an IC50 value at A␤42 in the low
nM range. It was not hepatotoxic (Thomson Reuters
Pharma, update of August 6, 2012).
BTA-EG4 (Johns Hopkins University and Georgetown University) is a benzothiazole aniline derivative
and amyloid-␤ synthesis inhibitor for the potential
treatment of Alzheimer’s disease (Thomson Reuters
Pharma, update of October 30, 2012). The structure
was not communicated.
C36 (Medisyn Technologies, Minnetonka, MN
in collaboration with the Mount Sinai School of
Medicine) is an A␤40 and A␤42 lowering small
molecule for the potential treatment of AD (Thomson
Reuters Pharma, update of December 6, 2011). The
structure was not disclosed.
Caprospinol (SP-233; Samaritan Pharmaceuticals,
Las Vegas, NV under license from Georgetown University) (Fig. 12), a spirostenol drug, blocked the
oligomerization of A␤42 exerting a direct effect
on mitochondria [1014–1017] (Thomson Reuters
Pharma, update of March 18, 2011).
Carvedilol is a launched unselective ␣1 , ␤1 and ␤2
blocker, which inhibited A␤ fibril formation [1018].
CLR01 (University of Duisburg-Essen, Rensselaer
Polytechnic Institute, NY and UCLA) (Fig. 12) is a
molecular tweezer, which binds to lysine residues with
micromolar affinity and interferes with a combination
of hydrophobic and electrostatic interactions that are
important in the self-assembly of most amyloidogenic
proteins including A␤, tau, and ␣-synuclein [1007,
1018–1024].
CLR-097(Clera Inc., Toronto) inhibited the process
of A␤ plaque formation (Thomson Reuters Pharma,
update of December 5, 2011). The structure was not
disclosed.
Cotinine, a natural metabolite of nicotine, may be a
potential new therapeutic agent against AD [1025]. It
reduced amyloid-␤ aggregation and improved memory
in Alzheimer’s disease mice [1725].
Daunomycin inhibited A␤ fibril formation [1018].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
DBT-1339 (Medifron, Seoul and licensee Daewoong, South Korea) (Fig. 12) is the lead compound
from A␤ protein deposition inhibitors (Thomson
Reuters Pharma, update of June 1, 2012).
Enoxaparin (Enox, a low molecular weight heparin) lowered brain A␤ load in a mouse model of AD
[1026]. It also improved cognition in APPSWE /PS1dE9
mice [1027, 1028].
GAG/carbohydrate compounds (ProteoTech,
Kirkland, WA) are glycosaminoglycan modulators
for the potential treatment of AD (Thomson Reuters
Pharma, update of June 7, 2012). Structures were not
disclosed.
Galantamine inhibited A␤ aggregation and cytotoxicity [1029].
haw-AD-14 (Hawthorn, Madison, Mississippi
under license from CoPlex) is an A␤ synthesis and tau
phosphorylation inhibitor (Thomson Reuters Pharma,
update of September 26, 2011). The structure was not
communicated.
HO-4160 (University of California at Davis)
(Fig. 12) is a spin-labeled fluorene compound that
specifically disrupted A␤ oligomers [1030].
Imipramine in part through inhibition of TNF-␣
prevented cognitive decline and A␤ accumulation in a
mouse model of AD [1031].
IPS-04001, IPS-04001 and IPS-04003 (InnoPharmaScreen, South Korea) is a specific inhibitor
of A␤ peptide and VEGF-165 interaction. By
June 2012, in vivo efficacy studies had shown a
significantly enhanced effect on the memory of
NSE-PS2/N141Ltransgenic mice (Thomson Reuters
Pharma, update of July 16, 2012). The structure were
not communicated.
KMS-88 series (Hanmi Pharmaceutical, South
Korea, the Korea Institute of Science and Technology
and Seoul National University) (Fig. 12) is a series of
aminostyryl-benzofuran derivatives inhibiting A␤ fibril formation [1032, 1033] (Thomson Reuters Pharma,
update of September 12, 2012).
Minocycline is a second generation tetracycline
that can effectively cross the blood-brain barrier.
It improved cognitive impairment in AD models
[1034]. It provided protection against A␤25-35 induced
alterations of the somatostatin signaling pathway
[1035, 1036]. It reduced microglial activation [1037,
1038]) and A␤ derived neuroinflammation [1039]. It
recovered MTT-formazan exocytosis impaired by A␤
[1040]. It reduced the development of abnormal tau
species in models of AD [1041–1043]. Minocycline
protected PC12 cells against NMDA-induced injury
via inhibiting 5-lipoxygenase activation [1044, 1045].
35
Minocycline improved negative symptoms in patients
with early schizophrenia [1046]. See also Part 2, Chapter 2.25. Drugs interacting with 5-Lipoxygenase.
NPT-4003 (Neuropore Therapies, San Diego CA) is
the lead of heterocyclic compounds that interfere with
amyloid-␤ aggregates. Detailed data were presented
at the ICAD Vancouver in July 2012 [1726]. (Thomson Reuters Pharma, update of July 16, 2012). The
structure was not communicated.
Rifampicin inhibited A␤ aggregation and neurotoxicity [1047–1049]. In a clinical trial in 101
mild-to-moderate AD patients, statistically significant
improvements in the ADAScog scores after treatment
with 300 mg rifampicin for three months were found
[988]. Rifampicin and caffeine caused an upregulation of LRP1 [1050]. The brain efflux index of A␤
in rifampicin and caffeine treated mice was significantly higher (82% and 80%, respectively) than the
brain efflux index of control mice (62%). It appears
that a yet to be identified transporter/receptor plays a
significant role in A␤ clearance, which is upregulated
by rifampicin and caffeine.
Rolitetracycline is effective as inhibitor of A␤ fibril
formation [1018].
SD-1002 (Synaptic Dynamics, Farmington CT) is a
lysosomal modulator that reduced protein deposition
of amyloid-␤1-42 oligomers for the potential treatment
of Alzheimer’s disease (Thomson Reuters Pharma,
updates of October 22, 2012). The structure was not
communicated.
SEN-1500 (Senexis, Cambridge, UK) (Fig. 12) and
follow-up compound SEN-1576 (structure not disclosed) are small molecule A␤ aggregation inhibitors
[1727] (Thomson Reuters Pharma, updates of March
23 and August 2, 2012, respectively).
Small molecule A␤ modulators (Asceneuron, a
spun-out of Merck Serono, Geneva, Switzerland) are
drugs for the potential treatment of AD (Thomson
Reuters Pharma, update of October 3, 2012). Structures
were not disclosed.
SP-08 (Samaritan Pharmaceuticals, Las Vegas, NV
under license from Georgetown University) (Fig. 12)
is an A␤ antagonist with neuroprotectant properties
(Thomson Reuters Pharma, update of March 18, 2011).
TAK-070 (University of Tokyo under license from
Takeda) is a ␤-secretase and A␤ aggregation inhibitor
(Thomson Reuters Pharma, update of July 10, 2012).
The structure was not communicated.
Tetracycline(s) showed anti-amyloidogenic activity in vitro [1051] and protected Caenorhabditis
elegans from A␤-induced toxicity by targeting
oligomers [1052].
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
For VP-20629 (Indole-3-propionic acid; OX1; INOX1; OXIGON, ViroPharma, Exton PA, under license
from Intellect Neurosciences under license from New
York University and Mindset BioPharmaceuticals;
Thomson Reuters Pharma, update of August 10, 2012),
see Chapter 11. Antioxidants.
AGT-160 (ArmaGen Technologies, Santa Monica, CA) is a recombinant IgG fusion protein
formed by the fusion of a single chain Fv antibody against A␤ plaque formation to the company’s
human insulin receptor-targeting monoclonal antibody Trojan horse for transport across the blood-brain
barrier for the potential detection and treatment of
AD (Thomson Reuters Pharma, update of January
23, 2012). See also Part 1. Chapter 1.16. Insulin
receptors.
EDN-OL1 (Edunn Biotechnology, St. Louis, Missouri under license from St. Louis University) is an
antisense oligonucleotide targeting A␤ production,
which improved memory and learning in three different AD mouse models. By February 2012, EDN-OL1
had demonstrated activity in patients with Down syndrome (Thomson Reuters Pharma, update of August
24, 2012).
NPT-001 (NeuroPhage Pharmaceuticals, Cambridge, MA) is a filamentous M13 bacteriophage that
disrupted plaque aggregation through binding of A␤.
Direct binding of M13 bacteriophage to fibrils of
aggregated A␤ was observed with high affinity of
4 nM. In an AD mouse model, A␤ plaques were
reduced by 70% after a single intracranial administration (Thomson Reuters Pharma, update of July 16,
2012).
Spheron-based therapeutics (Nymox Pharmaceutical Corp., Quebec) are compounds capable of
blocking the transformation of human spherons into
plaques [1053, 1054] (Thomson Reuters Pharma,
update of February 22, 2012).
A␤-aggregation inhibitor research programs were
ongoing at Elan [1055], at GrenPharma [1056], at GSK
[1057, 1058], at Johnson & Johnson [1059], at Pfizer
[1060], at Pharmacia-Farmitalia Carlo Erba [1061] and
at Scios [1062].
Excellent papers on A␤ aggregation inhibitors from
universities were presented (in chronological order)
1995: [1063], 1996: [1064], 1997: [1065, 1066], 2001:
[1067], 2002: [563, 1068], 2004: [1069, 1070], 2005:
[1071–1073], 2006: [1074–1082], 2007: [1083–1094],
2008: [745, 1043, 1095, 1096, 1097–1105] 2009:
[1106–1113], 2010: [391, 551, 980, 1114–1117], 2011:
[549, 643, 1118–1122] and 2012: [1033, 1123–1129,
1728].
Excellent papers on theoretical calculations on
A␤-aggregation inhibitors were published (in chronological order) 2006: [1130, 1131], 2008: [1066,
1132–1134], 2009: [1135–1137], 2011: [1138, 1139]
[1140, 1141], 2012: [1142–1144].
The Phase III development of tramiprosate
(3-amino-1-propanesulfonic acid, homo-taurine, NC531, Alzhemed, Cerebril; Bellus Health, former
Neurochem), an orally available glycosaminoglycan mimetic, was terminated in 2007 [1145–1151].
The compound was launched as a nutraceutical for
memory protection [1152]. Also the development of
ALS-499 and ALS-633 (Advanced Life Sciences,
in collaboration with Argonne National Laboratory), amyloid beta aggregation inhibitor (Zyentia),
amyloid oligomer specific antagonists (Treventis),
amyloid protein deposition inhibitor (ProteoTech),
AN-531 (Athena Neurosciences, now Elan Pharmaceuticals), AS-602704 (Ac-FPFFD-NH2 , Merck
Serono [1153]), beta amyloid aggregation inhibitors
(Cortex, Elan, Hybridon, Oceanix, Queens University
at Kingston and University of Wisconsin-Madison),
beta-amyloid modulators (Inflame Therapeutics,
Neuro-Hitech and Q-RNA), beta-amyloid precursor protein modulators (SIBIA Neurosciences in
collaboration with BMS), beta amyloid synthesis
inhibitors (BTG), CLR-01 (Clear Therapeutics, a
spin-off from UCLA), CT-500 (Creabilis Therapeutics), ID-1135 and ID-1567 (Bellus Health), lysosomal
modulators (Synaptic dynamics), MPI-442690 and
MPI-442691 (Myriad Genetics in collaboration with
the Mayo Clinic), NC-503 and NC-531 (Neurochem; Bellus Health), NHT-0112 (Neuro-Hitech),
NOX-A42 (Noxxon Pharma), NVP-AAM147 and
NVP-AAM155 (Novartis), phenserine-based amyloid inhibitors (Message Pharmaceuticals), PPI-368,
PPI-558 and PPI-1019 (Apan; all Praecis Pharmaceuticals [953, 957]), PTI-777 (ProteoTech),
Reumacon (Meda under license from Conpharm),
Ro-47-1816-001, Ro-65-7652-000, Ro-65-8564-001
and Ro-8815-001 (Roche), RS-1178 (BGC-20-1178;
Senexis under license from BTG under license
from Sankyo [1154]), RS-0406 (BGC-20-0406;
Senexis under license from BTG under license from
Sankyo [1155–1158]) and RS-0466 (Sankyo), RX-AD
(Rimonyx Pharmaceuticals), SAN-61 and SAN-161
(Sanomune, a subsidiary of DiaMedica), Semapimod
(CNI-1493; Cytokine PharmaSciences, CPSI, formerly Cytokine Networks), a cytokine inhibitor, which
inhibited A␤ production, plaque formation and cognitive deterioration in an animal model of AD [39, 40,
1729]), SEN-304, SEN-606, SEN-1186, SEN-1203,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
and SEN-1329 (Senexis), SIB-1848 (SIBIA Neurosciences, now Merck and Bristol-Myers Squibb),
SKF-746532 (SmithKline Beecham, now GSK),
synthetic anti-beta sheet peptides (Mayo Foundation), THUR-24 (Thuris Corp.), transthyretin
(Research Foundation of the State University of New
York), and of VIP-SSM (University of Illinois) was
terminated.
Ligands interacting with amyloid-β
Since the discovery of the 11 C-PiB-PET ligand,
tremendous progress has been made in the development of new PET ligands. Considerable evidence
suggests that A␤ deposition precedes decline in cognition [1159, 1160]. The development of PET amyloid-␤
imaging agents was described [1730].
11 C-PiB (University Pittsburgh) (Fig. 13) had a
KD = 1.4 nM for AD frontal cortex and KD = 4.7 nM
for A␤ fibrils and did not bind to neurofibrillary tangles [1161]. The log P value is 1.2 [1162]. Patients
with AD typically showed a marked 11 C-PiB retention (with a significant 1.5 to 2-fold increase) in
cortical areas known to contain large amounts of
A␤ plaques [1163–1165]. 11 C-PiB positivity in MCI
indicated already advanced A␤ pathology [1166].
Significant correlations between 11 C-PiB retention
and CSF biomarkers were found in MCI patients
[1167]. Clinical severity of AD measured by the
Clinical Dementia Rating scale sum of boxes correlated with 11 C-PiB uptake in PET [1168]. 11 C-PiB
imaging of human immunodeficiency virus-associated
neurocognitive disorder was described [1169]. For a
direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170] for
a comparison between Pittsburgh Compound B and
Florbetapir see [1731]. Longitudinal imaging of AD
pathology with 11 C-PiB, 18 F-FDDNP, and 18 F-FDG
was described [1171–1173]. For the prediction of cognitive decline via PET of brain A␤ and tau, see [1174].
The clinical perspective of imaging of cerebral A␤
plaques was discussed [1175, 1205]. The correspondence between in vivo 11 C-PiB-PET and postmortem
assessment of plaques was discussed [1176]. Imaging brain amyloid in nondemented adults with Down
syndrome using Pittsburgh Compound B was reported
[1732].
Fred Van Leuven and coworkers carried out a systematic evaluation of the isomeric compounds with
the OH groups attached in 4, 5, and 7 positions. The
5-hydroxy analogue had the most favorable in vivo
pharmacokinetics in brain [1177, 1178].
18 F-Florbetapir
37
(18 F-AV-45; Amyvid; Avid
Radiopharmaceuticals, Philadelphia, PA, a subsidiary
of Eli Lilly, under license from the University of Pennsylvania) (Fig. 13) is a launched 18 F PET imaging agent
targeting A␤. It had a Ki of 2.87 nM, did not bind to
tau, and can easily be labeled with 18 F by an automated
synthesis [1179–1187]. By March 2010, more than
700 patients were enrolled in a Phase III trial presumed
to be the 18 F-AV-45-A07 study. Several clinical papers
appeared describing imaging with 18 F-Florbetapir
[1188–1195]. Correlations between 18 F-Florpetapir
and FDG images were reported [1196]. 18 F-Florpetapir
is useful to quantify brain amyloid load [1197]. For
a direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170]; for a
clinical comparison of 18 F-Florbetapir and 18 F-FDG
PET in patients with AD and controls, see [1198]. A
prospective cohort study was described [1199].
A longitudinal assessment of 18-month of cognitive
decline in mild cognitive impairment and Alzheimer’s
disease patients using florbetapir was communicated
[1733]. “From Alois to Amyvid” see [1734]. PET
imaging was also carried out in a murine model of
amyloid-␤ plaque deposition [1735].
FDA approved 18 F-Florpetapir as a PET imaging agent to estimate A␤ neuritic plaque density in
patients with cognitive impairment on April 6, 2012.
Lilly launched the imaging agent in June 2012. The
compound will be manufactured and distributed by
Cardinal Health [1200] (Thomson Reuters Pharma,
update of September 17, 2012).
18 F-Florbetaben (18 F-BAY 94-9172; 18 F-AV1/ZK; Piramal Healthcare, Mumbai, India from an
asset acquisition from Bayer under license from Avid
Pharmaceuticals and the University of Pennsylvania)
(Fig. 13) is the phenyl analogue of florbetapir. It has
a Ki of 2.22 nM [1181]. In November 2009, a Phase
III clinical trial in AD patients (n = 292) began to
assess safety and efficacy of florbetaben to detect
or exclude cerebral A␤. Data from clinical studies
were reported [1201–1208]. An in vitro characterization was disclosed [1736]. The one-step radiosynthesis
was described [1209], as was the radiation dosimetry
[1210]. In the NCT01138111 trial, 18 F-Florbetaben
PET imaging was studied in MCI patients. For a
direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170]; for
a comparison of 11 C-PiB and 18 F-Florbetaben, see
[1211]; for the impact of 18 F-Florbetaben PET imaging on confidence in early diagnosis of AD, see [1212]
(Thomson Reuters Pharma, update of September 6,
2012).
38
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 13. Radioligands for PET scans of amyloid-␤.
18 F-Flutemetamol (GE-067; GE Healthcare, Chal-
font, UK and Universities of Pittsburgh and Uppsala)
(Fig. 13) has a Ki of 0.74 nM [1181]. Results of a
Phase I study were reported [1213], as were results
of a Phase II study [1214, 1215]. In December 2009,
a Phase III trial sponsored by GE Healthcare was initiated in the US. By April 2010, Phase III trials were
also underway in Europe. In April 2012, preliminary
data from the two Phase III studies in terminally ill
patients and young healthy subjects were reported.
Data showed that the primary endpoint was met.
Patients (who underwent brain autopsy) showed concordance between 18 F-Flutemetamol PET images and
AD-associated A␤ brain pathology and healthy subjects showed concordance with the known lack of brain
A␤. The association between in vivo 18 F-Flutemetamol
PET imaging and in vivo cerebral cortical histopathology was described [1216], as was a combination of
biomarkers PET 18 F-Flutemetamol and MRI [1217].
For a direct comparison of 11 C-PiB, 18 F-Florbetapir,
18 F-Florbetaben, and 18 F-Flutemetamol, see [1170].
Binary classification of 18 F-Flutemetamol PET using
machine learning was disclosed [1218]. The pharmacokinetics of 18 F-Flutemetamol in wild-type rodents
were reported [1219] (Thomson Reuters Pharma,
update of October 3, 2012).
18 F-AZD-4694 (Navidea Biopharmaceuticals,
Dublin, Ohio, formerly Neoprobe Corporation under
license from AstraZeneca) is an i.v. PET ligand for the
potential imaging of A␤ depositions in AD in Phase
II development [1220]. In December 2011, a Phase III
program was planned to start in early 2013 (Thomson
Reuters Pharma, update of September 21, 2012). The
structure was not communicated. For syntheses of
additional 18 F-ligands of AstraZeneca see [1737].
BAY-1006578 (Bayer) is in Phase I clinical trials in
Finland and Sweden since June 2010 (n = 36). By October 2011, the trial was completed (Thomson Reuters
Pharma, update of April 30, 2012). The structure was
not communicated. A potential follow up compound is
BAY-1008472 [1221].
123 I-MNI-168 (Institute for Neurodegenerative
Disorders, IND, New Haven, CT) is a SPECT ligand to detect A␤ deposition in patients with AD. A
Phase I clinical trial was initiated in the US in January
2009 (n = 34). In February 2011, the trial was terminated (Thomson Reuters Pharma, update of February
10, 2012). The structure was not communicated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
18 F-MNI-558
(Molecular NeuroImaging in collaboration with the Institute for Neuro-degenerative
Disorders, IND, New Haven, CT) is a PET agent that
binds A␤. The compound was in a Phase 0 trial in AD
patients and in volunteers (n = 10) from October 2010
to July 2011 (Thomson Reuters Pharma, update of
April 30, 2012). The structure was not communicated.
11 C-BF-227 (Fig. 14) was used for amyloid PET
imaging [1222–1225], for PET imaging of ␣-synuclein
deposition [1226, 1227], and for in vivo detection of
prion amyloid plaques [1228].
123 I-DRM-106 (Fujifilm Pharma) (Fig. 14) is
a radioiodinated imidazopyridine derivative for the
potential use as SPECT imaging agent for A␤ for the
diagnosis of AD (Thomson Reuters Pharma, update of
September 21, 2011).
18 F-Hexethal (Pfizer, under license from the University of Aberdeen), a barbiturate derivative, is an A␤
imaging agent (Thomson Reuters Pharma, update of
September 24, 2012).
11 C-SB-13 (Fig. 14) was evaluated first in postmortem brain tissues [1229] and in AD patients [1230].
18 F-Florbetapir dimer (Avid Radiopharmaceuticals, Philadelphia, PA, Eli Lilly) is a PET imaging
agent for the potential diagnosis of cerebral amyloid
angiopathy [1231] (Thomson Reuters Pharma, update
of May 8, 2012).
Dicyanovinylnaphtalenes were described for neuroimaging of A␤ [1232]. Also 18 F-labeled benzoxazoles [1233] and 18 F-labeled 2-pyridinylbenzoxazoles
and 2-pyridinylbenzothiazoles were presented for PET
imaging of A␤ plaques [1234].
The development of 11 C-AZD-2184 and 11 CAZD-2995 (both AstraZeneca [1235–1237, 1738])
and 18 F-FDDNP (Siemens Medical Solutions Molecular Imaging and UCLA) (Fig. 14) was terminated.
18 F-FDDNP was the first PET tracer used in vivo for
detection of cerebral A␤ plaques in 2002 [1238]. 18 FFDDNP binds to A␤ and neurofibrillary tangles in AD,
to prion plaques in Creutzfeldt-Jakob disease, to A␤
deposits in cerebral amyloid angiopathy, and to Lewy
bodies in PD and DLB [1161]. It was used for measuring amyloid-␤ and tau levels in adults with Down’s
syndrome [1739]. The ligand is still used for prediction of cognitive decline [1174, 1740]. Longitudinal
imaging of AD pathology using 11 C-PiB, 18 F-FDDNP,
and 18 F-FDG PET was described [1239]. 18 F-FDDNP
PET allowed a prediction of cognitive decline based
on hemispheric cortical surface maps [1240].
123 I-IMPY (Avid Radiopharmaceuticals, Philadelphia, PA, under license from University of Pennsylvania, Fig. 14) is a SPECT ligand for imaging studies
39
[1241, 1242]. Its Ki is 15 nM [1243]. The safety and
biodistribution was evaluated [1244]. The signal-tonoise ratio for plaque labeling is not as robust as that
of 11 C-PiB. 11 C-PiB showed a S/N ratio of about 2.5,
while 123 I-IMPY displayed a ratio of 1.8–2.0, between
30 and 50 min after an i.v. injection [1181]. Its development was terminated.
The development of amyloid binding PET
ligands (Aventis), fluoropegylated indolyl-phenylacetylenes (Avid Radio-pharmaceuticals), 11 C-6-MeBTA (University of Pittsburgh), and of 18 F-SMIBRW372 (Siemens Medical Solutions Molecular Imaging) was terminated.
Inhibitor of serum amyloid P component binding
The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of A␤ deposits
and contributes to the pathogenesis of amyloidosis
[1245–1247].
Ro-63-8695 (CPHPC; Pentraxin Therapeutics, London under license from Roche) (Fig. 14) is a
competitive inhibitor of serum amyloid P component
binding to amyloid fibrils (IC50 = 0.9 ␮M). First results
from in vivo mouse and human studies have been communicated [1245, 1248–1250]. In addition, Pentraxin
Therapeutics and GSK are investigating a combination
of CPHPC with a humanized antibody for the potential
treatment of amyloidosis (Thomson Reuters Pharma,
update of March 22, 2012).
Vaccines against amyloid-β
AN-1792 (AIP-001; Elan and American Home
Products, later Wyeth, now Pfizer) was the first vaccine against AD in clinical trials. The antigen was
synthetic A␤42 , which was administered with QS-21
from the Stimulon family of saponins purified from the
bark of Quillaja saponaria as adjuvant [1251, 1252].
The multicenter double-blind Phase IIa study in the
US and Europe involving 375 patients with mild-tomoderate AD started in the third quarter of 2001.
Treatment of patients with AN-1792 plus adjuvant
and the adjuvant alone as placebo was in a ratio of
4 : 1. 18 patients developed meningoencephalitis probably due to an inappropriate T cell activation and/or
the proinflammatory Th1 type of adjuvant. The study
was discontinued in March 2002 [1253]. Nevertheless, many important data could be collected. From
129 patients immunized with the drug, 25 were classified as antibody responders after 4.5 years. These
patients showed significantly slower decline on the
40
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 14. PET and SPECT ligands.
disability assessment for dementia and a significant
difference on a dependence scale compared to placebotreated patients. Antibody responders also showed less
of a decline in a memory test. The scientific harvest
of this single clinical trial is listed in chronological
order [1254–1286] (Thomson Reuters Pharma, update
of August 24, 2012).
Affitope AD-02 (Affiris, Vienna AT and licensee
GlaxoSmithKline Biologicals) is a six amino acid peptide vaccine targeting the N-terminus of A␤ only, when
it is free. The adjuvant is aluminum hydroxide. The
antibody response is focused exclusively on A␤ and
did not show crossreactivity to A␤PP [1287, 1288]. A
European Phase II clinical trial in 420 patients in Austria, Germany, France, the Czech Republic, Slovakia,
and Croatia started in April 2010 (Thomson Reuters
Pharma, update of August 1, 2012).
CAD-106 (Cytos Biotechnology, Zurich and Novartis) is an A␤1-6 peptide linked to a Q␤ virus-like
particle for the s.c. treatment of patients with AD.
One Phase IIa trial was initiated in July 2008 (n = 27),
and a second Phase IIa trial was started in October
2008 (n = 30). The safety, tolerability, and antibody
response of active A␤ immunotherapy with CAD106 in patients with AD was published [1289]. For
comments, see [1290, 1291]. It was found that 80%
of the patients involved in the trial developed their
own protective antibodies against A␤ without suffering any side-effects over the three years of the study.
The researchers believe that the CAD106 vaccine is a
tolerable treatment for patients with mild-to-moderate
AD. In March 2010, a randomized, placebo-controlled,
multicenter, Phase II trial began in patients (n = 120)
in the US, Canada, and Europe with mild AD [1276,
1292, 1293]. Preclinical results in transgenic mice were
presented [1294] (Thomson Reuters Pharma, update of
July 26, 2012).
Vanutide cridificar (ACC-001, PF-05236806;
Janssen Alzheimer Immunotherapy, Dublin, Ireland acquiring Elan’s Alzheimer’s Immunotherapy
Program and Pfizer) is a peptide fragment of A␤ conjugated to the mutated diphtheria toxin protein CRM197.
The adjuvant is QS-21. In May 2007, a randomized,
multicenter, double-blind, placebo-controlled, parallel
assignment, safety/tolerability/immunogenicity Phase
II trial in patients with mild-to-moderate AD (n = 56)
began [1295]. In July 2009, Pfizer began a multicenter, randomized, unblinded, QS-21-adjuvanted,
long-term, Phase II trial of vanutide cridificar (3, 10,
and 30 microg, im) in patients (n = 160) in the US.
At that time the estimated study completion date was
September 2014. In August 2009, an additional study
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
was initiated in Japanese subjects (n = 32) [1276]
(Thomson Reuters Pharma, update of August 13,
2012).
ACI-24 (AC Immune, Lausanne, Switzerland) is an
A␤1-15 peptide to which on both ends two lysines
were attached, which are tetrapalmitoylated on the
␧-nitrogens. The antigen is embedded in a liposome membrane. Adjuvant is a mixture of the lipids
DMPC, DMPG, cholesterol, and MPLA in a ratio
of 9 : 1 : 7 : 0.06, respectively [1296, 1297]. The drug
restored memory defects of transgenic AD mice.
The IgF subclasses of the antibodies generated from
the vaccine were mostly IgG2b indicating a noninflammatory Th2 isotype. CD and NMR revealed
predominantly ␤-sheet conformation. The drug is
currently evaluated in a Phase I/II clinical trial in
Denmark, Finland, and Sweden (Thomson Reuters
Pharma, update of June 19, 2012).
Affitope-AD-03 (Affiris, Vienna, Austria and
licensee GlaxoSmithKline Biologicals) entered a
Phase I clinical trial in October 2010. In November 2011, the study was completed (Thomson Reuters
Pharma, update of April 4, 2012).
UB-311 (United Biomedical, Hauppauge, NY) is
an intramuscularly administered vaccine targeting Nterminal amino acids 1-14 of A␤ in Phase I clinical
trials in Taiwan in patients with mild-to-moderate AD
(n = 18) [1298] (Thomson Reuters Pharma, update of
June 25, 2012).
V-950 (Merck, Whitehouse Station, NJ) is an
N-terminal A␤ peptide conjugated to an aluminumcontaining adjuvant with or without ISCOMATRIX
(an adjuvant containing saponin, cholesterol, and
phospholipids) [1299]. Mild-to-moderate AD patients
(n = 124) received six injections/year of increasing
doses of either placebo or V-950 in the presence or
absence of varying concentrations of ISCOMATRIX
in Phase I clinical trials in the US and Sweden over
a four year period [1276] (Thomson Reuters Pharma,
update of February 24, 2012).
There are numerous vaccine preparations in preclinical evaluation (in alphabetical order):
ABvac40 and ABvac42 (Araclon Biotech,
Zaragoza, Spain) are active therapeutic antibody
vaccines awaiting approval for clinical trials [1741]
(Thomson Reuters Pharma, update of June 25, 2012).
ADepVac (Ichor Medical Systems, San Diego, CA
in collaboration with the University of California at
Irvine and the Institute for Molecular Medicine) is a
DNA vaccine using the TriGrid electroporation technology [1300] (Thomson Reuters Pharma, update of
July 13, 2012).
41
ALZ-101 (Alzinova, Goteborg, Sweden, a spin-off
of MIVAC Development) is a specific oligomerdirected therapeutic vaccine (Thomson Reuters
Pharma, update of July 18, 2012).
ALZ-301 (Alzinova, Goteborg, Sweden, a spin-off
of MIVAC Development) is an A␤40 oligomer targeted replacement therapy (Thomson Reuters Pharma,
update of July 18, 2012).
Alzheimer’s disease vaccine (VLP Biotech, San
Diego CA) is a vaccine that activates antibodies against
A␤ protein (Thomson Reuters Pharma, update of May
3, 2012).
Amyloid-␤ 3-10 DNA vaccination (China Medical University, Shenyang) suggested a potential new
treatment for AD [1301–1305].
Active immunization with Ankyrin G, a neuronal
cytoskeletal protein, with Freund’s adjuvant complete
of arcA␤ mice reduced A␤ pathology [1306].
BAN-2203 (BioArctic Neuroscience, Stockholm,
Sweden) is an immunotherapeutic vaccine targeting
A␤ protofibrils (Thomson Reuters Pharma, update of
January 7, 2011).
BBS-1 BACE inhibitor mAb vaccine (Nasvax,
Ness Ziona, IL under license from Ramot at Tel Aviv
University) is based on a lead mAb candidate blocking
␤-site-1, which inhibited the ability of BACE to cleave
A␤PP (Thomson Reuters Pharma, update of July 30,
2012).
C12 (Pharma Bio, Moscow, Russia) is a program
of therapeutic vaccines comprised of synthetic peptide
fragments of the ␣7 nicotinic acetylcholine receptor
used to generate antibodies that block A␤ binding to
neurons (Thomson Reuters Pharma, update of March
29, 2012).
EB-101 (Atlas Pharmaceuticals, Sunnyvale, CA)
is a synthetic human A␤42 /sphingosine-1-phosphate/
liposome vaccine (Thomson Reuters Pharma, update
of July 27, 2012).
A T cell-based vaccination with Glatimer acetate
of AD double-transgenic (A␤PP/PS1) mice resulted
in decreased plaque formation and induction of
neurogenesis. Dendritic-like (CD11c) cells produced
insulin-like growth factor 1 [1307].
MER-5101 (Mercia Pharma, Scarsdale, NY) is a
vaccine comprised of an A␤ peptide conjugate coupled
to an immunogenic carrier protein and the company’s Th2-biased adjuvant MAS-1 (Thomson Reuters
Pharma, update of January 27, 2012).
Mimovax (MV-01; Affiris, Vienna AT) is an
AFFITOPE-based vaccine targeting truncated and
modified forms of A␤ (Thomson Reuters Pharma,
update of April 2, 2012).
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
NU-700 (Nuron Biotech, Exton, PA under license
from Vitruvian BioMedical under license from the
University of Texas Southwestern Medical Center) is
an adjuvant free, gene-base (DNA) A␤42 vaccine for
the potential treatment or prevention of AD (Thomson
Reuters Pharma, update of May 22, 2012).
Recombinant adenovirus vector vaccine (Vaxin,
Birmingham, AL in collaboration with AnC Bio,
South Korea) elicited an immune response against A␤
using Crucell’s PER.C6 technology for the potential
intranasal treatment of AD (Thomson Reuters Pharma,
update of May 2, 2012).
RV-03 (Intellect Neurosciences, New York, NY) is
a peptide vaccine developed using the RECALL-VAX
technology targeting both A␤ and a truncated delta tau
protein (Thomson Reuters Pharma, update of August
21, 2012).
SeV-amyloid beta RNA vaccine (DNAVEC,
Tsukuba, Japan) is an intranasal vaccine comprising
a Sendai virus vector encoding the A␤ gene [1308]
(Thomson Reuters Pharma, update of September 21,
2011).
Excellent papers on A␤ vaccines from universities
were presented (in chronological order) 2000: [1309,
1310]; 2001: [1311]; 2004: A␤1-42 gene vaccination
[1312]; 2005: a synthetic universal Th cell pan HLA
DR epitope, pan HLA DR-binding peptide (PADRE),
in which the PADRE-A␤1-15 sequence lacks the T cell
epitope of A␤ [1313]; 2006: an A␤ derivative in alum
adjuvant [1314], an intranasal dendrimeric A␤1-15 vaccine [1315–1319]; 2007: an oral vaccination using
a recombinant adeno-associated viral vector carrying A␤ cDNA (AAV/A␤) [1320], a transcutaneous
administration of aggregated A␤1-42 plus the adjuvant
cholera toxin [1321], a mannan-A␤28 conjugate [1322,
1323]; 2008: a DNA epitope vaccine that expresses epitopes of A␤42 [1324]; 2009: K6 A␤1-30-NH2 in alum
adjuvant [1325], an A␤1-33-MAP peptide to markedly
reduce intracellular A␤ deposits [1326], K6A␤1-30 for
immunizations of old primates [1327], A␤1-42 vaccinations also reducing mouse tau pathology [1328];
2010: an oral vaccination with GFP-A␤ [1329], immunization of aged beagle dogs with aggregated A␤1-42
formulated in an alum adjuvant [1330], active immunization with A␤1-42 emulsified in CFA containing
Mycobacterium tuberulosis extract [1331], lowering
of A␤ plaque burden by the SDPM1 peptide, a 20
amino acid peptide bound by cysteines that binds
tetramer forms of A␤1-40 and A␤1-42 amyloids [1332];
2011: two novel anti-A␤ vaccines consisting of virus
like particles [1333], the identification of the shortest A␤-peptide generating specific antibodies [1334];
2012: preventive immunization of aged primates
[1335].
Excellent reviews on A␤ vaccines have been provided (in chronological order) 2001: [1336], [1337],
2002: [1257, 1338–1341], 2003: [1342]), 2004:
[1343]), 2005: [1344–1346], 2006: [1347–1349],
[1350], 2007: [1351–1355], 2008: [1356–1359],
2009: [1282, 1360–1363], 2010: [1364–1370], 2011:
[1371], [1372–1374], and 2012: [23].
A clinical review of active and passive immunotherapeutic approaches in AD targeting A␤ was presented
[1375, 1376].
The development of A␤ retroparticles (University
of Heidelberg and Novartis [1377]), Abloid (Virionics), ACC-002 (Elan), AFFITOPE AD-01 (Affiris),
Alzheimer’s vaccine (Lundbeck under license from
Pharmexa), Alzheimer’s vaccine (Mindset BioPharmaceuticals), Alzheimer’s disease vaccines (University of South Florida and University of New Mexico),
anti-amyloid-␤ vaccines (Wyeth, now Pfizer and
Janssen Alzheimer Immunotherapy), DNA vaccine
(University of Texas, Southwestern Medical Center), immunotherapy vaccine (Prana Biotechnology),
KNX-Vaccine3A (Kinexis under license from the University of California at Irvine), PEVIPRO (Pevion
Biotech [1378]), PX-106 (Lundbeck/Pharmexa), and
RV-01 (Intellect Neurosciences) was terminated.
Antibodies against amyloid-β
Bapineuzumab (AAB-001; Janssen Alzheimer
Immunotherapy, Dublin, Ireland following the acquisition of Elan’s Alzheimer’s Immunotherapy Program
and Pfizer) is a humanized monoclonal antibody raised
against eight amino acids in the N-terminus of A␤ for
the potential i.v. and s.c. treatment of AD. A Phase III
clinical study started in December 2007. The Phase III
program included two trials in ApoE4-positive patients
(n = 800 in the US and EU) and two in ApoE4-negative
patients (n = 1,250 in the US and EU) for 18 months
each and three extension studies for both ApoE4 and
non-ApoE4 arms with three doses, 0.5, 1, and 2 mg/kg.
The highest dose had to be abandoned due to vasogenic
edema safety concerns. One extension study started in
July 2009 (n = 1,350), two additional extension studies
in December 2009 in the EU and Australia (n = 800 and
1,000, respectively). Clinical results from the Phase
I and Phase II studies were reported [1276, 1361,
1379–1382] as was a 11 C-PiB PET assessment [1383]
and the effects on CSF biomarkers [1384]. Reviews on
bapineuzumab were published (in chronological order)
[23, 1385–1392]. For the scientific basis see the Nature
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Medicine paper [1393]. The pharmacokinetic profile of
125 I-labeled 3D6, the mouse parent antibody of bapineuzumab, in transgenic mice was reported [1742].
In July 2012, Pfizer reported that the ’302 study in
ApoE4 carriers did not meet its primary endpoints.
Pfizer, Johnson & Johnson, and Elan announced that
development of i.v. bapineuzumab was terminated
(Thomson Reuters Pharma, update of September 18,
2012).
Solanezumab (LY-20622430; Lilly) is a middomain humanized monoclonal antibody selective for
soluble A␤. Three Phase III studies were initiated
in patients with mild-to-moderate AD (n = 1,000) in
May 2009, patients received 400 mg of solanezumab
or placebo i.v. every 4 weeks for 80 weeks.
First results were disclosed (in chronological order)
[1276, 1394–1398]. Safety and biomarker effects of
solanezumab in patients with AD was communicated
[1399]. Solanezumab failed to meet the cognitive and
functional primary endpoints of two Phase III AD trials. But it showed a significant reduction in cognitive
decline in patients with mild AD. The open-label
EXPEDITION-EXT extension trial, which is fully
enrolled, will continue as planned (Thomson Reuters
Pharma, update of September 7, 2012).
Gantenerumab (R-1450; Roche under license from
MorphoSys) is a human anti-A␤ monoclonal antibody. A Phase II clinical trial in Canada (n = 360)
was initiated in January 2011. Prodromal AD patients
(NCT01224106) are to receive 105 or 225 mg administered by s.c. injection every 4 weeks for 104 weeks to
evaluate effects on cognition and functioning, safety,
and pharmacokinetics. In June 2012, the trial was
expanded to a Phase II/III trial. The trial size will be
increased from 360 to 770 participants. The mechanism of A␤ removal was described [1400, 1401]. An
expert opinion was provided [1402] (Thomson Reuters
Pharma, update of September 5, 2012).
Crenezumab (MABT-5102A; RG-7412; Genentech under license from AC Immune, Lausanne,
Switzerland) is an anti-A␤ humanized monoclonal antibody as a conformation-specific, passive
immunotherapy for the potential i.v or s.c. treatment of
AD. A Phase II clinical trial (n = 372; NCT01397578)
was initiated in April 2011. The first Alzheimer’s Prevention Initiative will study the effects of crenezumab
in 300 people from a large family in Columbia with
a rare genetic mutation that typically triggers AD
symptoms around age of 45. It is a collaboration
between the National Institutes of Health (NIH), Banner’s Alzheimer’s Institute, and Genentech over five
years starting in 2013. Data and findings will be shared
43
publicly after the study completion. The scientific basis
for the selection of crenezumab was published recently
[1403] (Thomson Reuters Pharma, update of September 5, 2012).
GSK-933776A (GSK) is a monoclonal antibody
for the i.v. treatment of AD and age-related macular
degeneration. A Phase II trial (n = 162) of age-related
macular degeneration started in the US in August
2011 (Thomson Reuters Pharma, update of August 24,
2012).
The topic intravenous immunoglobulins as a treatment for AD, the rationale and current evidence was
described in reviews [1404, 1405, 1743].
Immune globulin intravenous human (IVIg;
launched as Gammagard in the US and as Kiovig
in Europe; Baxter International, Deerfield, IL) is
a highly purified solvent/detergent-treated, sterile,
freeze-dried preparation derived from human plasma
for the treatment of primary immunodeficiency disease. This pool of human immunoglobulins obtained
from healthy donors contains naturally occurring
anti-A␤ antibodies. In a Phase II trial in 24 patients,
the eight-person placebo group worsened, whereas
the 16 treated patients improved moderately on both
cognitive and quality-of-life measures over the first
6 months [1406–1408]. A Phase III clinical trial in
AD patients enrolling 390 patients was initiated in
September 2008. Trial completion is expected by the
end of 2012 (NCT00818662, NCT00299988) [1276].
The first report of long-term (three-year) stabilization
of AD symptoms with IVIG (Gammagard, Baxter),
including no decline on measures of cognition, memory, daily functioning, and mood, was reported in
July 2012 at the Alzheimer’s Association International
Conference in Vancouver. Sales in 2011 amounted to
1,541 million USD. For preclinical data, see [1409,
1410] (Thomson Reuters Pharma, update of October
3, 2012).
Octagam (Octapharma, Lachen, Switzerland) is
a 10% liquid intravenous immunoglobulin launched
for the treatment of primary immunodeficiency. By
December 2008, a double-blind, randomized, Phase
II clinical trial (NCT 00812565) in 58 patients with
AD had been initiated in the US. Clinical data were
presented at the AAIC in Paris in July 2011 (Thomson
Reuters Pharma, update of April 3, 2012).
Flebogamma DIF 10% (or 5%) (Grifols SA,
Barcelona) is a 10% (or 5%) double inactivated and
filtered immunoglobulin therapy for the treatment of
primary immunodeficiency. Data were presented on a
single-center, open-label, pilot study on the use of Flebogamma DIF 0.5 g/kg i.v., q2w for 6 months in AD
44
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
patients (n = 4) (Thomson Reuters Pharma, update of
March 23, 2012).
BAN-2401 (Eisai under license from Bioarctic
Neuroscience, Stockholm, Sweden) is a humanized
monoclonal antibody that targets the large soluble
amyloid product (protofibril A␤). A Phase I trial in 80
patients with mild-to-moderate AD began in September 2010. Eisai plans to co-administer BAN-2401 with
donepezil and memantine (Thomson Reuters Pharma,
update of July 19, 2012).
NI-101 (BIIB-037, BART; Biogen Idec, Weston,
MA under license from Neuroimmune Therapeutics,
Zurich Switzerland) is a recombinant chimeric human
IgG1 mAb targeted against A␤. A Phase I clinical trial
(n = 40) in patients with mild-to-moderate AD started
in the US in July 2011 (Thomson Reuters Pharma,
update of September 24, 2012).
PF-05236812 (AAB-003; Janssen Alzheimer Immunotherapy and Pfizer) is a humanized monoclonal
antibody targeted against A␤. In October 2010, a randomized, double-blind, placebo-controlled, adaptive,
Phase I trial was initiated in patients with mild-tomoderate AD (n = 80) in the US [1411] (Thomson
Reuters Pharma, update of August 13, 2012).
RN6G (Rinat Neuroscience Corp., New York, now
Pfizer) is an anti-A␤ antibody for the potential i.v.
treatment of age-related macular degeneration in Phase
I trial (n = 45) since April 2009 in the US. In April
2012, a randomized, double-blind, placebo-controlled,
Phase II study was planned in patients with geographic
atrophy secondary to age-related macular degeneration
(expected n = 276) to assess the safety and efficacy of
RN6G [1412] (Thomson Reuters Pharma, update of
September 11, 2012).
SAR-228810 (sanofi) is an anti-protofibrillar A␤
monoclonal antibody. A randomized, double-blind,
placebo-controlled, Phase I trial in patients with mildto-moderate AD (n = 48) was initiated in Sweden in
January 2012. The study is scheduled to complete in
December 2013 (Thomson Reuters Pharma, update of
July 27, 2012).
There are currently many antibodies for the potential treatment of AD and closely related diseases in
preclinical evaluation (in alphabetical order):
4E10 (Prana Biotechnology, Parkville, Australia) is
a monoclonal antibody targeting a proprietary pathological A␤ target epitope (Thomson Reuters Pharma,
update of November 2, 2011).
6F6 (GSK) is an anti-A␤ monoclonal antibody for
the potential treatment of age-related macular degeneration (Thomson Reuters Pharma, update of June 9,
2011).
9D5 (University of Göttingen, MBM ScienceBridge) targets pyro-Glu-A␤ peptide oligomers for the
potential diagnosis and treatment of AD [1413] (Thomson Reuters Pharma, update of August 7, 2011).
A-887755 (Abbott Laboratories) is an A␤,
oligomer-selective, mouse monoclonal antibody
generated using a homogenous, synthetic A␤20-42
oligomer peptide (Thomson Reuters Pharma, update
of February 27, 2012).
A-992401 (Abbott Laboratories) is a mAb targeting the receptor for advanced glycation-end-products
(Thomson Reuters Pharma, update of December 1,
2010).
Ab40-4-42 (Ilsung Pharmaceutical, Seoul) is a
biological therapeutic, which acted by inhibiting
A␤ aggregation and cytotoxicity (Thomson Reuters
Pharma, update of May 14, 2012).
ACU-193 (Acumen Pharmaceuticals, Livermore
CA) is a monoclonal antibody against amyloid-derived
diffusible ligands (Thomson Reuters Pharma, update
of August 16, 2012).
AD-0802 (Bioarctic Neuroscience, Stockholm,
Sweden) is a humanized mAb with affinity for binding
to A␤ protofibrils. It is a potential follow-up compound
to BAN-2401 (vide supra) (Thomson Reuters Pharma,
update of January 7, 2011).
AGT-160 (ArmaGen Technologies, Santa Monica,
CA) is a recombinant IgG fusion protein formed by the
fusion of a single chain Fv antibody against A␤ plaque
formation to the company’s human insulin receptortargeting monoclonal antibody Trojan horse for the
transport across the blood-brain barrier. A 1 mg/kg i.v.
dose of AGT-160 was administered twice a week for
12 weeks to transgenic AD mice resulting in a 40%
decrease in the brain concentration of A␤ (Thomson
Reuters Pharma, update of January 23, 2012). See also
Part 1. Chapter 1.16. Drugs interacting with the insulin
receptor.
ALZ-201 (Alzinova, Goteborg, Sweden, a spinoff of MIVAC Development) is an oligomer-specific
A␤ monoclonal antibody (Thomson Reuters Pharma,
update of July 20, 2012).
Amyloid
precursor
protein
C-terminal
fragment-targeted monoclonal antibodies (Ecole
Polytechnique Fédérale de Lausanne, EPFL) is
a monoclonal antibody targeted to the 99 amino
acid C-terminal fragment of A␤PP (A␤PP-C99)
(Thomson Reuters Pharma, update of March 31,
2011).
Anti-amyloid beta antibodies (Kyowa Hakko
Kirin under license from Immunas Pharma, OncoTherapy Science Inc.) are antibodies targeting A␤
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
oligomers (Thomson Reuters Pharma, update of
August 6, 2012).
Brain-targeted BACE1 antibody (Genentech,
Roche Holding) is a bi-specific antibody against
BACE1 and the transferrin receptor to allow transcytosis across the blood-brain barrier [1414, 1415]
(Thomson Reuters Pharma, update of May 14, 2012).
This technique was pioneered by Prof. William M.
Pardridge of UCLA [1416–1422].
CPHPC+antibody (Pentraxin, London and GSK) is
a combination of CPHPC, which lowers blood levels of
serum amyloid P component (see Chapter 16.2) and a
humanized antibody for the treatment of amyloidosis
[1249] (Thomson Reuters Pharma, update of March
22, 2012).
DLX-212 (Delenex Therapeutics, Zurich, Switzerland) is an anti-A␤ antibody fragment (Thomson
Reuters Pharma, update of March 29, 2012).
Fully human monoclonal antibodies (Intrexon,
Blacksburg VI after its acquisition of Immunologix)
are targeting A␤ plaques for the potential treatment
of AD (Thomson Reuters Pharma, update of June 13,
2012).
IN-N01 (Intellect Neurosciences under license from
Immuno-Biological Laboratories, IBL, New York,
NY) is an antibody drug conjugate consisting of a
A␤-specific humanized mAb employing its ANTISENILIN technology, for the potential treatment of
AD, glaucoma, age-related macular degeneration and
traumatic brain injury. In September 2012, Intellect
planned to conduct studies in combination with tau
mAbs TOC-1and TauC3 (Thomson Reuters Pharma,
update of September 20, 2012).
IN-N01-OX2 (Intellect Neurosciences, New York,
NY) is a humanized IgG4 monoclonal antibody conjugated to melatonin developed using its CONJUMABA technology for the potential treatment of age-related
macular degeneration and Alzheimer’s disease (Thomson Reuters Pharma, update of October 2, 2012).
Lpathomab (LT-3015; Lpath Inc., San Diego,
CA) is a systemic formulation of a humanized antilysophosphatidic acid monoclonal antibody for the
potential treatment of fibrosis, ocular inflammation,
and CNS disorders including AD [1423] (Thomson
Reuters Pharma, update of August 28, 2012).
MDT-2007 (Medronic, Minneapolis, MN) is a
humanized anti-A␤ monoclonal antibody, the humanized version of the mouse mAb 6E10 (Thomson
Reuters Pharma, update of January 6, 2012).
Nanobody therapeutics (Ablynx, Gent Belgium
and licensee Boehringer Ingelheim) are naturallyoccurring single chain antibodies of Camelidae. In
45
April 2012, a CTA was submitted to European regulatory authorities for a Phase I study (Thomson Reuters
Pharma, update of August 23, 2012).
NEOD-001 (Onclave Therapeutics, Dublin, Ireland
and Neotope Biosciences, South San Francisco, CA
and Elan) is a proprietary monoclonal antibody for
the potential treatment of AL amyloidosis. In February
2012, the drug was awarded Orphan status by the FDA
for AA amyloidosis and AL amyloidosis (Thomson
Reuters Pharma, update of June 27, 2012).
STC-103 (STC Biologics, Cambridge, MA) is a
novel Fc fusion protein therapeutic for the potential
treatment of AD (Thomson Reuters Pharma, update of
August 10, 2012).
Excellent papers on A␤ antibodies from universities
and basic research from companies were presented (in
chronological order) 1996: [1424], 1997: [1425]; 2000:
[1393]; 2005: [1426, 1427], 2006: [1428, 1429], 2007:
[1430–1441], 2008: [1442–1447], 2009: [1448–1454],
2010: [1366, 1455–1460], 2011: [1461–1465], 2012:
[1466, 1467, 1744].
Excellent reviews were provided (in chronological order) 2006: [1350], 2007: [1468–1470], 2008:
[1356, 1358, 1471, 1472], 2009: [1360, 1361,
1473–1475], 2010: [1369]; 2011: [23, 1371, 1388,
1389, 1476–1478], 2012: [1479]. The challenge
of adverse effects of immunotherapy for AD was
addressed [1480].
A clinical review of active and passive immunotherapeutic approaches in AD targeting A␤ was presented
[1375, 1376].
The development of 11A1 (a monoclonal antibody against the toxic conformer of A␤42 ; Tokyo
Metropolitan Institute of Gerontology, Kyoto University and Immuno-Biological Laboratories), A-11
(A␤ deposition-inhibiting antibody; Kinexis under
license from the University of California), AAB002 (Janssen Alzheimer Immunotherapy and Pfizer),
ABP-102 (Abiogen Pharma; a catalytic monoclonal
antibody, an abzyme), ACU-5A5, ACU-0101979
and huC091 (Acumen Pharmaceuticals), anti-Abeta
monoclonal antibodies (Mapp Biopharmaceutical in
collaboration with Johns Hopkins University), the
anti-amyloid beta antibody therapy targeting specific forms of the A␤ parenchymal plaque (sanofi under
license from Rockefeller University), anticalin (Pieris,
an antibody against residues 16-26 of A␤), AZD3102 (AstraZeneca), bapineuzumab (AAB-001;
Janssen Alzheimer Immuno-therapy and Pfizer), beta
amyloid deposition-inhibiting antibodies (amyloidosis, Kinexis), beta amyloid-targeting antibodies
(Mindset BioPharmaceuticals), encapsulated scFv-
46
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
beta 1-expressing cells targeting the EFRH tetrapeptide region of A␤ (scFv-beta 1; Novartis in collaboration with the Institute for Research in Biomedicine
and the Ecole Polytechnique Fédérale de Lausanne), ESBA-212 (ESBA Tech, Nestlé, a humanized
single-chain antibody directed against A␤), KNXMonoclonal204 and KNX-Monoclonal205 (Kinexis
under license from the University of California at
Irvine), m266 (an antibody specific for the central
domain of A␤; Lilly [1481, 1482]), and ponezumab
(PF-4360365; RN-1219; RI-1219; Rinat Neuroscience
and Pfizer) [1276, 1483–1485] a humanized monoclonal antibody specific for the C-terminus of A␤40 ,
was terminated.
DRUGS INTERACTING WITH TAU
A hallmark of the AD brain is the presence
of inclusions within neurons that are comprised of
fibrils formed from hyperphosphorylated microtubulestabilizing protein tau (paired helical filaments and
neurofibrillary tangles [1486–1489]. The formation
of misfolded multimeric tau species is believed to
contribute to the progressive neuron loss and cognitive impairments of AD [1490]. Tau suppression in
a neurodegenerative mouse model improved memory
function [1491]. The precise composition of the neurotoxic species Tau-P* is not defined yet [1486]. The
levels of early multimeric tau-aggregates that preceded
the neurofibrillary tangles were found to correlate with
memory deficits [1492]. The sites of phosphorylation and the involved kinases were compiled [1493,
1494]. The tau phosphorylation pathway genes were
described [1495]. Although A␤ plaques may play a
key role in AD pathogenesis the severity of cognitive
impairment correlated best with the burden of neurofibrillary tangles described in an exhaustive review
of the literature [1496, 956]. A␤ and tau influence each
other in the mediation of toxicity. A␤ formation in
A␤PP transgenic mice caused hyperphosphorylation
of tau, whereas there was no overt A␤ plaque pathology in tau transgenic mice. Immunization against A␤
in triple transgenic mice resulted in reduced levels
of hyperphosphorylated tau. Tau reduction prevented
A␤ induced defects in the axonal transport of mitochondria. Combination of these data led to the two
step tau axis hypothesis of AD [1497–1499]. First,
postsynaptic toxicity of A␤ is tau-dependent, because
tau interacts with FYN [1500], which is localized to
the dendritic compartment, where it phosphorylates
the NMDA receptor subunit 2B, mediates their inter-
action with the postsynaptic density protein 95, an
interaction required for A␤ toxicity and second, A␤
triggers progressively increased phosphorylation of tau
compromising the binding of tau to microtubules leading to increasing dendritic tau levels [1501]. For a
very instructive figure depicting these interactions, see
[1502]. The synaptic accumulation of hyperphosphorylated tau oligomers is associated with dysfunction of
the ubiquitin-proteasome system [1503].
A cascade of biomarkers was proposed: A␤ precedes
tau-mediated neuronal injury; A␤- and tau-mediated
abnormalities precede neuroimaging biomarkers such
as changes in hippocampal or ventricular volumetry
measured by MRI; and all of these precede cognitive change marked by progressive deterioration
in episodic memory and other cognitive domains
such as executive functions abilities [1504–1506].
In a longitudinal study in 172 participants (AD:
n = 41; MCI: n = 85; and normal controls: n = 46),
the temporal relations among the four classes of
biomarkers were examined. Results indicated that CSF
A␤ effects on cognition change were substantially
attenuated by CSF tau and measures of brain structure
and function and CSF tau effects on cognitive change
were attenuated by neuroimaging variables. Contrary
to hypotheses, CSF A␤ and CSF tau were observed to
have independent effects on neuroimaging and CSF tau
had a direct effect on baseline cognition independent
of brain structure and function [1507].
Small molecules preventing tau aggregation
TRx-0014 (methylthioninium chloride, methylene
blue, Rember; TauRx Therapeutics, Singapore, a spinout from the University of Aberdeen) (Fig. 15) is a
tau protein aggregation inhibitor. In August 2004, a
placebo-controlled, dose-ranging Phase II trial was
initiated in subjects (n = 275) with AD associated
dementia in the UK. The doses were 30, 60, or 100 mg
tid. In July 2007, a Phase II open-label continuation
study of two doses of 30 or 60 mg tid gelatin capsules started for 52 weeks. The drug reduced cognitive
decline by 81% over 1 year and no significant loss
of cognitive function was seen over 19 months [1508,
1509]. In November 2010, the EC granted the drug
Orphan status for frontotemporal dementia, progressive non-fluent aphasia and progressive supranuclear
palsy. In February 2012, an open-label trial in patients
with frontotemporal dementia was ongoing. For the
preclinical characterization, see [1510–1516]. Only
when levels of soluble tau protein were concomitantly
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
reduced by a very high concentration of methylene blue
cognitive improvement was observed in a mouse model
of human tauopathy [1517]. Methylene blue also inhibited the aggregation of A␤ [1518, 1519] (Thomson
Reuters Pharma, update of September 10, 2012).
LMT-X (TauRx Therapeutics, Singapore) is a
potential follow-up compound and prodrug of Rember.
In September 2012, a Phase III study for frontotemporal dementia began in 180 subjects for 12 months.
In October 2012 two global phase III studies were
initiated for AD. The first study will involve 833
patients with mild to moderate Alzheimer’s disease
over 12 months, while the second study will include
500 patients with mild Alzheimer’s disease over 18
months. The clinical trials will be conducted in parallel
and on a global basis including sites in Australia, Belgium, Canada, Finland, Germany, Italy, Russia, Spain,
Netherlands, Singapore, Malaysia, Taiwan, US and UK
(Thomson Reuters Pharma, update of November 21,
2012). The structure was not communicated.
PBT-2 (Prana Biotechnology, Parkville, Australia)
(see Fig. 9) is an oral zinc ionophore metal-protein
attenuating compound that reduced levels of soluble A␤ and tau hyperphosphorylation in a Phase IIa
study in AD patients. (Thomson Reuters Pharma,
update of October 2, 2012) See also Chapter 12. Metal
Chelators.
Tideglusib (NP-12, NP-031112; Nypta; Noscira,
previously known as Neuropharma, Madrid) (Fig. 15)
is a GSK-3␤ inhibitor in Phase II clinical trials for AD.
Results from the 309-patient study were expected by
October 2012. First positive results of a clinical pilot
study were reported [1520] (Thomson Reuters Pharma,
update of July 23, 2012). See also Part 2, Chapter 2.16.
Drugs interacting with GSK-3␤.
BMS-241027 (Bristol-Myers Squibb) is a small
molecule microtubule stabilizer aimed at preventing
the production of abnormal tau protein. A randomized,
double-blind, placebo-controlled Phase I study was initiated in patients with mild AD (expected n = 100) in
the US and in Europe in March 2012 (Thomson Reuters
Pharma, update of August 6, 2012). The structure was
not communicated.
PP2A stimulator (Se-015; Ve-015; Velacor Therapeutics, Victoria, Australia) is a selenium derivative
acting as protein phosphatase 2A (PP2A) stimulator
resulting in dephosphorylation of Akt kinase and tau.
By February 2011, a Phase I trial had been completed
and the company received the approval to initiate a
Phase IIa trial in AD patients in Australia (Thomson
Reuters Pharma, update of February 10, 2011). The
structure has not been communicated.
47
There are many compounds inhibiting tau aggregation in preclinical evaluation (in alphabetical
order):
A␤/tau protein aggregation inhibitors (CNRS,
FIST SA, Paris, France) are investigated for the potential treatment of AD (Thomson Reuters Pharma, update
of August 24, 2012). The structures of the compounds
were not communicated.
Astemizole and Lansoprazole have been found to
selectively interact with tau polymers [1521].
Berberine attenuated tau hyperphosphorylation in
HEK293 cells [1745].
Bezafibrate (Bezalip, Bezatol; Boehringer
Mannheim, now Roche, co-marketing with Kissei
Pharmaceuticals, launched 1977) (Fig. 15), a drug
for the treatment of hyperlipidemia, is a pan-PPAR
agonist, which improved behavioral deficits and tau
pathology in P301S mice exerting a preventive effect
[1522].
BLV-0703 (BLV-200703; Bioalvo, Lisbon, Portugal) (Fig. 15) is a tau aggregation inhibitor in
preclinical development (Thomson Reuters Pharma,
update of May 9, 2011).
Epothilone D improved microtubule density, axonal
integrity and cognition in a transgenic mouse model of
tauopathy [1523].
Fulvic acid inhibited aggregation and promoted the
disassembly of tau fibrils associated with AD [639].
Insulin intranasal ameliorated tau hyperphosphorylation in a rat model of type 2 diabetes [1524].
L-3-n-butylphthalide reduced tau phosphorylation
and improved cognitive deficits in A␤PP/PS1Alzheimer’s transgenic mice [1746].
NBB BSc3504 (TU Darmstadt and Max-PlanckUnit for Structural Molecular Biology Hamburg)
(Fig. 15) is a N -benzylidene-benzohydrazide
showing remarkable tau aggregation inhibition
(IC50 > 0.97 ␮M) and paired helical filament
depolymerization (DC50 > 1.14 ␮M), but poor
affinity towards A␤1-42 fibrils (IC50 > 33 ␮M) [1525].
NC-11813 (Eli Lilly and Nymirum, Ann Arbor, MI)
is an inhibitor of tau exon 10 splicing, which stabilized
the tau splice regulatory element (Thomson Reuters
Pharma, update of August 10, 2012). The structure was
not communicated.
NP-111001 derivatives (Noscira, Madrid) act as tau
phosphorylation inhibitors (Thomson Reuters Pharma,
update of January 12, 2012). The structures were not
communicated.
NPT-002 (NeuroPhage Pharmaceuticals, Cambridge, MA) targets A␤ and tau aggregates for the
potential treatment of AD (Thomson Reuters Pharma,
48
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 15. Molecules preventing tau aggregation.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
update of July 16, 2012). The structure was not communicated.
Protein phosphatase methylesterase 1 (PME1)
inhibitors (Signum Biosciences and GSK) are small
molecules blocking the enzyme which demethylates
PP2A. Normally PP2A is almost all methylated, but in
Alzheimer’s disease PP2A methylation is reduced in
half. The structural mechanism of demethylation and
inactivation of protein phosphatase 2a was described
[1747–1749] (Thomson Reuters Pharma, update
of November 15, 2012). The structures were not
communicated.
Protein phosphatase 2A stimulators (Cognosci,
Research Triangle Park, NC) inhibit the formation of
apoE/inhibitor 2 of PP2A (I2PP2A) complex. The topic protein phosphatases and AD was reviewed [1526,
1527] (Thomson Reuters Pharma, update of February
24, 2012). The structures were not communicated.
ReS3-T, ReS8-T, ReS10-T and ReS19-T
(reMYND, a spin-off from the University of Leuven,
Belgium and licensee Roche) are four series of tau
detoxifying compounds targeting tau-mediated cytotoxicity (Thomson Reuters Pharma, update of September 14, 2012). The structures were not communicated.
The ReS9-S7 and ReS12-S programs (reMYND,
a spin-off from the University of Leuven, Belgium
and licensee Roche) investigate the attenuation of
the cytotoxic effects of ␣-synuclein aggregation in
dopaminergic neurons for the potential treatment of
PD (Thomson Reuters Pharma, update of September
14, 2012). The structures were not communicated.
SIG-1012 (Cognion) and SIG-1106 (Signum Biosciences, Monmouth Junction NJ in collaboration with
Princeton Univ.) are phosphoprotein 2A modulators
and presumed to also include the PP2A methylesterase
1 inhibitor eicosanoyl-5-hydroxytryptamide (EHT), all
extracted from coffee and acting as tau aggregation
inhibitors. (Thomson Reuters Pharma, update of October 05, 2012). The structures were not communicated.
Small molecule Tau protein modulators
(Asceneuron, a spun-out of Merck Serono, Geneva,
Switzerland) are drugs for the potential treatment of
AD (Thomson Reuters Pharma, update of October 3,
2012). Structures were not disclosed.
Small molecule tau modulators (Yuma Therapeutics, Brookline, MA) target neurofibrillary tangles
resulting from abnormal forms of the protein tau
(Thomson Reuters Pharma, update of March 29, 2011).
Sodium selenate mitigated tau pathology and functional deficits in AD models [1528].
Tau aggregation inhibitors (Catholic University of
Leuven, Belgium) are currently in the preclinical Phase
49
(Thomson Reuters Pharma, update of July 30, 2012).
Structures were not communicated.
Tau aggregation inhibitors (ProteoTech, Kirkland, WA) have a potential for the treatment of AD
(Thomson Reuters Pharma, update of July 30, 2012).
Structures were not communicated.
Tau oligomer inhibitors (Oligomerix, New York,
NY) are presumably curcumin derivatives (Thomson
Reuters Pharma, update of April 24, 2012).
Tau phosphorylation inhibitors (ProQinase,
Freiburg im Breisgau, Germany) (Fig. 15) reduced
in vivo GSK-3␤ selective phosphorylation of
Ser396/Ser404 and Ser262 in the brains of triple
transgenic mice after i.p. administration. It appears
that the development was terminated (Thomson
Reuters Pharma update of October 11, 2012).
Therapeutic program (B & C Biopharm and
Equispharm, both South Korea) is targeting tau
kinase (Thomson Reuters Pharma update of May 18,
2012).
Thiamet-G (Simon Fraser University) is a potent
inhibitor of human O-GlcNAcase (Ki = 21 nM)
(Fig. 15) and efficiently reduced phosphorylation of
tau at Thr231, Ser396, and Ser422 in both rat cortex and hippocampus [1529–1533]. For commentaries,
see [1534, 1535]. See also Part 2, Chapter 2.27. Drugs
interacting with O-GlcNAcase.
THQ-4S and THQ-55 (Fig. 15) interact specifically
with oligomeric forms of tau inhibiting their assembly
into AD filaments [1536, 1537].
TRx-0237 (TauRx Therapeutics, Singapore) is the
lead compound of second-generation tau aggregation
inhibitors. Safety and efficacy studies in AD and frontotemporal dementia patients are planned for 2012
(Thomson Reuters Pharma, update of September 25,
2012). The structure was not communicated.
Tubastatin A (Fig. 15) is a potent and selective
HDAC6 inhibitor [1750]. Chronic tubastatin treatment
for two months decreased total tau levels in rtg4510
mice [1751].
Natural products as a source of tau-targeting drugs
were described [1538].
Excellent papers on small molecule inhibitors of
tau aggregation were published by researchers at
universities (in chronological order) 2004: [1539],
2005: [1540] (benzothiazoles such as N-744, Fig. 15),
[1541, 1542] 2006: [1543]; 2007: [1544–1550], 2009:
[1551–1555], 2010: [1556, 1557], 2011: [1558, 1559],
2012: [1560, 1561].
Excellent reviews on tau-focused drug discovery
for AD were presented (in chronological order)
2000: [1562]; 2002: [1563], 2006: [1564], 2007:
50
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1565], 2008: [1566–1569], 2009: [1570, 1571], 2010:
[1572–1574], 2011: [1575, 1576] [1577, 1578], 2012:
[1579–1581]. Interestingly, synergistic interactions
between repeats in tau protein and A␤ were described
[1582].
The development of the tau aggregation inhibitors
aminothienopyridazines (University of Pennsylvania), AZD-1080 (AstraZeneca), BPU-410 and
BPU-430 (Champions Biotechnology under license
from Johns Hopkins University), LDN-33960 (a
striatal-enriched protein tyrosine phosphatase (STEP)
inhibitor, Yale University), NHT-0112 (NeuroHitech), protein phosphatase methylesterase 1
(PME1) inhibitors (Scripps Research Institute and
Massachusetts Institute of Technology), SDGIT200801 and SDGII-T200801 (both Bioalvo),
SRN-003-556 (SIRENADE Pharmaceuticals) and of
TRx-0037 (TauRx) were terminated.
Ligands interacting with tau
T-777, T-807, and T-808 (Siemens Medical Solution Molecular Imaging) (Fig. 15) are tau-binding
molecules as PET tracers for the diagnosis of AD.
They are benz[4,5]imidazo[1,2-a]pyrimidines. 18 FT808 displayed a high level of binding affinity
(Kd = 22 nM) and good selectivity for tau aggregates
over A␤ plaques [1583] (Thomson Reuters Pharma,
update of September 19, 2011).
Novel in vivo tau imaging agents 18 F-THK-523
(University of Melbourne) [1584] and 11 C-THK-951
(Tohoku University) (both Fig. 15) were published
[1585] after preliminary results of 2005 [1752] (Thomson Reuters Pharma, update of September 219, 2012).
The University of Melbourne is investigating
18 F labeled arylquinoline derivatives, such as
18 F-THK-5105, 18 F-THK-5116, 18 F-THK-5117, and
18 F-THK-5125 for the potential use in imaging tau
deposition in neurofibrillary tangles for AD (Thomson Reuters Pharma, update of June 13, 2012). The
structures were not communicated.
Researchers of Amersham (GE Healthcare) published a patent describing ligands with an exceptional
selectivity to tau: compound 18 (Fig. 15): Kd = 0.9 nM
for tau and Kd = 30 ␮M for A␤1-40 [1586].
A 125 I-3-oxindole derivative stained neurofibrillary tangles in AD brain sections [1587].
Also bis(arylvinyl)pyrazines, -pyrimidines, and
-pyridazines were described as imaging agents for tau
fibrils and A␤ plaques [1588] as were 2-styrylindolium
based fluorescent probes [1753].
Research toward tau imaging was reviewed [1553,
1589, 1590] stating that ligand polarizability contributes to tau fibril binding affinity.
Vaccines against tau
Recombinant misfolded truncated tau protein vaccine (Axon Neurosciences, Vienna, Austria)
attenuated pathology in vivo in a transgenic rat model
of tauopathy (Thomson Reuters Pharma, update of
February 17, 2011).
RV-03 (Intellect Neurosciences, New York, NY)
is a peptide vaccine developed using the RECALLVAX technology targeting both the A␤ and a truncated
delta tau protein (Thomson Reuters Pharma, update of
August 21, 2012).
Phosphorylated tau peptides were used to immunize
transgenic mice to produce robust anti-neurofibrillary
tangle effects [1591].
The development of the chimeric peptide vaccine
RV-02 (Intellect Neurosciences) was terminated.
Antibodies against tau and α-synuclein
Humanized tau monoclonal antibodies (AC
Immune, Lausanne, Switzerland) had high specific
affinity binding to pTau. The compound was outlicensed to Genentech (Thomson Reuters Pharma,
update of June 19, 2012).
Lilly presented data on passive immunization with
anti-tau antibodies in two transgenic mouse models
[1754].
NI-105 (Biogen Idec, Weston, MA through the
acquisition of Panima, previously a subsidiary of
Neurimmune Therapeutics, Zurich Switzerland) is a
human recombinant monoclonal antibody targeted to
tau protein created using Neurimmune’s reverse translational medicine platform (Thomson Reuters Pharma,
update of May 4, 2012).
PD-0805 (Bioarctic Neuroscience, Stockholm,
Sweden) is a monoclonal antibody targeting ␣synuclein for the potential treatment of PD and DLB
(Thomson Reuters Pharma, update of September 2,
2011).
Pfizer presented the first X-ray structure of an avian
antibody to its cognate phosphopeptide pT231/pS235
at 1.9 Å resolution [1755].
T01-OX2 (Intellect Neurosciences, New York, NY)
is an antibody drug conjugate that consists of a mAb
targeting oligomeric forms of tau protein conjugated
to melatonin (Thomson Reuters Pharma, update of
August 17, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
TauC3 monoclonal antibody (Intellect Neurosciences, New York, NY under license from
Northwestern University) is targeting the neoepitope
tauC3 (Thomson Reuters Pharma, update of September
20, 2012).
Tau protein modulator (iPierian, South San
Francisco, CA) is a monoclonal antibody for the
potential treatment of AD, frontotemporal dementia
and progressive supranuclear palsy (Thomson Reuters
Pharma, update of May 22, 2012).
Tau-targeted antibody therapy (Neotope Biosciences, South San Francisco, CA and Elan) is a
monoclonal antibody targeted to tau (Thomson Reuters
Pharma, update of August 13, 2012).
TOC-1 (Intellect Neurosciences, New York under
license from Northwestern University) is a tauoligomer-targeting monoclonal antibody [1592, 1593]
(Thomson Reuters Pharma, update of September 20,
2012).
The detection of naturally occurring anti-tau antibodies was described [1594].
Already in 1985 monoclonal antibodies to AD neurofibrillary tangles were described [1595]. Excellent
papers on passive immunization targeting pathological
phospho-tau protein were published (in chronological order) 2005: [1596], 2007: [1597], 2008: [1598,
1599], 2009: [1600, 1601], 2010: [1602, 1603], 2011:
[1604–1607], 2012: [1756].
The development of TTRY78F (University of
Porto), an anti-transthyretin monoclonal antibody, was
terminated.
STEM CELLS
Substantial progress has been achieved in research
of stem cells for the potential treatment of AD
communicated in chronological order: 2000: [1608],
2001: [1609–1611], 2006: [1612–1614], 2007: [1615,
1616], 2008: [1617, 1618], 2009: [1619–1622], 2010:
[1623–1630], 2011: [1631–1635], 2012: [1636–1642,
1757].
Human neural stem cells overexpressing choline
acetyltransferase restored cognitive function of kainicacid-induced learning and memory deficits in rats
[1643, 1644]. Neural stem cells reduced hippocampal tau and reelin accumulation [1645]. Intracerebral
transplantation of bone marrow-derived mesenchymal
stem cells reduced A␤ deposition and rescued memory deficits in AD mice by modulation of immune
responses [1626]. Neural stem cells improved cognition via BDNF in a transgenic model of AD
51
[1646–1648]. Human neural stem cells genetically
modified to express human NGF gene restored
cognition in mice [1649]. Human neural stem cells
genetically modified to overexpress BDNF promote
functional recovery and neuroprotection in a mouse
stroke model [1650]. Neural stem cells improved learning and memory in rats with AD [1651] and improved
neuronal survival in cultured postmortem brain tissue
from aged and AD patients [1652].
Induced pluripotent stem cells may be used to model
patient-specific AD in vitro [1653, 1654]. For a commentary, see [1655]; to model pathology in Down
syndrome [1656] and in HD [1657]. They may create new opportunities for disease modeling and drug
discovery [1758].
GDNF/BDNF-producing glial and brain-derived
stem cells (NurOwn; BrainStorm Cell Therapeutics,
New York, NY) is investigated as a potential treatment
of PD, sciatica, and multiple sclerosis [1658, 1659].
A Phase I/II clinical trial in ALS patients started in
June 2011 in Israel. In January 2012 positive data were
reported (Thomson Reuters Pharma, update of July 24,
2012).
Human neural stem cell therapy (HuCNS-SC;
StemCells, Newark, CA, formerly CytoTherapeutics
under license from NeuroSperes) is a proprietary transplantable human neural stem cell therapy for the
potential treatment of spinal cord injury, age-related
macular degeneration, and AD. Human neural stem
cells induced functional myelination in mice [1759]
and in the human brain [1760]. A Phase II trial for
spinal cord injury was initiated in Switzerland in March
2011. The neuroprotective effects in retinal degeneration were described [1660] (Thomson Reuters Pharma,
update of September 28, 2012).
Mesenchymal bone marrow-derived stem cell
therapy (Stemedica Cell Technologies, San Diego,
CA) is being developed for the intravenous treatment
of ischemic stroke in Phase I/II since February 2011
in the US (n = 35). The study was expected to be completed in February 2013 (Thomson Reuters Pharma,
update of April 11, 2012).
NSI-189 (Neuralstem, Rockville, MD, in collaboration with Japanese licensee Summit Pharmaceuticals)
(Fig. 16) is an orally bioavailable small-molecule neurogenesis stimulator in Phase I, which was completed
in October 2011. The FDA approved the Phase Ib trial
in December 2011 (three cohorts of eight patients each
). In June 2012, the first patients were dosed (Thomson
Reuters Pharma, update of September 28, 2012).
NSI-566RSC (Neuralstem, Rockville, MD) are
human neural stem cells including spinal cord stem
52
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 16. A neurogenesis stimulator and two SV2A ligands.
cells for the potential injectable treatment of ALS,
stroke, HD, and AD. Long-distance growth and connectivity of neural stem cells after severe spinal cord
injury were investigated [1661]. A Phase I clinical
trial for ALS started in January 2010 in the US. The
results of a Phase I trial in 12 ALS patients receiving
lumbar intraspinal injection of neural stem cells were
described [1662] (Thomson Reuters Pharma, update of
September 28, 2012).
Neurostem-AD (Medipost, South Korea) is an
umbilical cord blood-derived mesenchymal stem cell
therapy, which regenerates nerve cells. A Phase I
trial has been initiated in February 2011 in patients
(expected n = 9) with dementia of AD-type (Thomson
Reuters Pharma, update of September 25, 2012).
There are several stem cell preparations in preclinical evaluation (in alphabetical order):
Adult mesenchymal precursor stem cell therapy
(Mesoblast, Melbourne, Australia and Cephalon, a
wholly-owned subsidiary of Teva) is evaluated for the
potential treatment of AD and PD and stroke (Thomson
Reuters Pharma, update of September 6, 2012).
Allogenic umbilical cord stem cell therapy
(U-CORD; CellPraxis Bioengenharia, Bela Vista,
Brazil) is investigated for the potential treatment
of Alzheimer’s disease. (Thomson Reuters Pharma,
update of November 07, 2012).
Brain-derived stem cell therapy (Celprogen, San
Pedro, CA, in collaboration with the Indiana University
School of Medicine) can be differentiated into neurons.
In vivo preclinical studies demonstrated improvement
in short and long term memory in AD experimental
models (Thomson Reuters Pharma, update of July 14,
2011).
CPG23NEUR (Celprogen, San Pedro, CA) derives
from cord blood stem cells, which are transdifferentiating into neuronal cells (Thomson Reuters
Pharma, update of January 30, 2012).
Glial progenitor cell therapy (Q Therapeutics, Salt
Lake City, UT) has the potential to replace myelin
on damaged neurons for the treatment of transverse
myelinitis, spinal cord injury, multiple sclerosis, PD,
and AD (Thomson Reuters Pharma, update of January
20, 2012).
Human neural progenitor cells (Cedars-Sinai
Medical Center, Los Angeles, CA), which secrete
growth factors including glial cell-derived neurotrophic factor, may be useful for the treatment of ALS
(Thomson Reuters Pharma, update of July 31, 2012).
Human umbilical cord blood cells (Saneron CCEL
Therapeutics, Tampa FL) are cerebroprotective agents
which showed cognition enhancing and amyloid-␤
reducing activities for the potential treatment of stroke
and Alzheimer’s disease (Thomson Reuters Pharma,
update of October 26, 2012).
NBI-18 (NeoCytex Biopharma, Covington, KY),
a heterocyclic pyrimidine derivative, is a stem cell
stimulator for the potential treatment of neurodegenerative diseases including ALS, AD, and PD (Thomson
Reuters Pharma, update of January 19, 2012). The
structure was not communicated.
Neural stem cell therapy (Stemedica Cell Technologies, San Diego, CA) is an allogeneic therapy
for the potential treatment of AD (Thomson Reuters
Pharma, update of February 22, 2012). Another
stem cell therapy is evaluated for spinal cord injury
(Thomson Reuters Pharma, update of February 28,
2012).
NeurotrophinCell (Living Cell Technologies,
Auckland, NZ) is an alginate-microencapsulated
porcine choroid plexus cell product for the potential
treatment of neurodegenerative diseases including HD,
PD, and dementia [1663, 1664] (Thomson Reuters
Pharma, update of May 16, 2012).
NGN-9079 (neural stem cell therapy; NeuroGeneration, Los Angeles, CA) is evaluated for the potential
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
treatment of AD. Transplantation of neuronal cells
into the brain was shown to improve and delay the
symptoms of AD in animal models (Thomson Reuters
Pharma, update of March 2, 2012).
ReN-004 (ReNeuron, Guildford, UK) is a neural
stem cell therapy for PD and AD (Thomson Reuters
Pharma, update of September 5, 2012).
ReN-005 (ReNeuron, Guildford, UK) is a neural
stem cell therapy for HD (Thomson Reuters Pharma,
update of December 24, 2010).
Stem cell therapeutics (Samaritan Pharmaceuticals, Las Vegas, NV) are non-embryonic neuronal stem
cell differentiation therapeutics including the naturally
occurring compounds SP-sc4 and SP-sc7 to induce
stem cell differentiation for the potential treatment of
AD (Thomson Reuters Pharma, update of March 16,
2011).
Allopregnanolone (University of Southern California, Los Angeles, CA) is a potent and highly efficacious
proliferative agent in vitro and in vivo of both rodent
and human neural stem cells [1665–1667].
Granulocyte colony-stimulating factor is known
to mobilize hematopoietic stem cells from the bone
marrow into the peripheral blood. Subcutaneous
administration of granulocyte colony-stimulating factor into two different A␤-induced AD mouse models
substantially rescued their cognitive/memory functions [1668].
Valproic acid can induce neurogenesis of neural
progenitor/stem cells both in vitro and in vivo via multiple signaling pathways [1669].
The development of GRNOPC-1 (Geron), oligodendrocyte precursor cells differentiated from a human
embryonic stem cell line that produce neurotrophic factors and remyelinate axons for the potential injectable
treatment of PD, stroke, AD, multiple sclerosis, and
spinal cord injury in Phase I since October 2010
was terminated. Also the development of the human
embryonic stem cell therapy (GRNIC-1, Geron),
the cell-based therapy MDA-200C (Medeia Therapeutics), NEBO-176 (Neuro Bioscience and RLI),
propentofylline (Endogenous Stem Cells Activators
(ESAI) under license from sanofi) and of stem cell
therapies for glaucoma, macular degeneration, PD,
traumatic brain injury, and vascular dementia (Stemedica) was terminated.
MISCELLANEOUS
Autophagy inducer JRP-900 (Prous Institute for
Biomedical Research, Barcelona) is investigated for
53
the potential treatment of neurodegenerative disease
including AD, ALS, HD, and PD (Thomson Reuters
Pharma, update of July 23, 2012). The structure
was not communicated. For reviews on autophagy in
Alzheimer’s disease and tauopathies see [1761–1764].
Cellular homeostasis modulator CNS-102 (Coyote Pharmaceuticals) acts on protein misfolding for
the potential treatment of AD, multiple sclerosis, and
ALS (Thomson Reuters Pharma, update of October 2,
2012). The structure was not communicated.
Glycan inhibitors (Stelic Institute, Tokyo) are
investigated for the potential treatment of Parkinson’s
and Alzheimer’s disease. An exhaustive review was
provided [1765]. (Thomson Reuters Pharma, update of
October 16, 2012). Structures were not communicated.
Macrophage migration inhibitory factor (MIF)
inhibitor INV-88 (Innovimmune Biotherapeutics,
New York) is investigated for the potential oral treatment of inflammatory diseases, central nervous system
diseases including Alzheimer’s disease and multiple
sclerosis and age-related macular degeneration (Thomson Reuters Pharma, update of October 18, 2012). The
structure was not communicated.
MicroRNA (miRNA) mimetics (University of
Göttingen, MBM Science) are evaluated for the potential diagnosis and treatment of memory impairment.
By June 2012, proof of concept was achieved in an
AD mouse model and in human AD patient samples.
The relationship of miRNAs in the brain and A␤ generation was discussed [1670] (Thomson Reuters Pharma,
update of August 7, 2012).
Proteasome-gating modulators are investigated
by Proteostasis Therapeutics, Cambridge, MA under
license from Harvard University for the potential treatment of neurodegenerative diseases including AD and
PD (Thomson Reuters Pharma, update of August 15,
2012).
Synaptic vesicle glycoprotein 2A (SV2A) ligand
levetiracetam (L-059, Keppra; UCB Pharma, Brussels, Belgium and Japanese licensee Otsuka) (Fig. 16)
is an antiepileptic drug launched in the US and EU
in 2000 and in Japan in 2010 [1671–1676]. It binds
to the same binding site as botulinum neurotoxin A
and tetanus neurotoxin [1677, 1678]. It is still unclear
how levetiracetam modulates SV2A’s function(s). It
inhibited presynaptic Ca2+ channels through an intracellular pathway [1679, 1680]. It may promote
glutamate uptake by increasing glutamate transporter
expression [1681]. There are hints that levetiracetam
may interact with GABAA receptors [1682–1684].
Levetiracetam had a positive impact on emotional
learning and memory in naı̈ve mice [1685] and
54
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
reversed cognitive deficits in hA␤PP transgenic mice
[1686]. Levetiracetam improved cognitive function in
drug-naı̈ve epilepsy patients [1687] and in children
aged 4 to 16 years [1688]. The sales of levetiracetam
reported by UCB for 2011 were USD 1,345 million and
by Otsuka, USD 60.5. An injectable formulation was
launched in the US in August 2006, an extended release
formulation in September 2008 (Thomson Reuters
Pharma, update of October 1, 2012).
Low-dose therapy Levetiracetam (AgeneBio,
Carmel, IN under license from John Hopkins University) is investigated for the potential treatment
of amnestic MCI (aMCI) in Phase II clinical trials since December 2009 in 144 aMCI patients in
the US. Reduction of hippocampal hyperactivity in
aMCI patients by using a low dose of levetiracetam
improved cognition [1766]. It appears that the development was terminated (Thomson Reuters Pharma,
update of September 7, 2011).
Brivaracetam (UCB-34714; Rikelta; UCB Pharma,
Brussels, Belgium) (Fig. 16), the n-propyl analogue
of levetiracetam, is an orally active ligand of synaptic
vesicle protein 2A (SV2A) currently in Phase III clinical trials for the treatment of epilepsy since November
2008 (n = 600). The study is expected to complete in
June 2015 [1689, 1690]. Its binding characteristics as
a high affinity SV2A ligand in rat, mouse and human
brain were reported [1691] as was its effect on the
inhibition of Na+ currents [1692]. Its neurocognitive
effects were similar to the ones of levetiracetam [1693,
1694] (Thomson Reuters Pharma, update of August 8,
2012).
The development of the second Phase III monoclonal antibody bapineuzumab (Janssen Alzheimer
Immunotherapy and Pfizer) was terminated.
The Phase III clinical trials of other A␤ PET
imaging agents, 18 F-florbetaben (Piramal) and 18 Fflutemetamol (GE Healthcare), may be successfully
completed by next year. The completion of Phase
III clinical trials of the VMAT2 PET ligand 18 Fflorbenazine (Avid Radiopharmaceuticals, Lilly) is
planned for September 2014.
Phase II clinical trials of other disease modifying drugs, of monoclonal antibodies against A␤
gantenerumab, crenezumab, GSK-93377A, intravenous immune globulin, and octagam, of vaccines
against A␤ AD-02, CAD-106, and vanutide cridificar and the PET ligand 18 F-AZD-4694 (Navidea)
will require several years. This applies also for the
Phase II clinical trials of small molecules preventing
A␤ aggregation or inhibiting formation of transthyretin
amyloid fibrils, such as doxycycline hyclate, ELND005, and SOM-0226 or preventing tau aggregation,
such as PBT-2, tideglusib, and TRx-0014.
Concerning drugs for palliative treatment of AD,
two Phase III compounds are currently frontrunners,
DP-b99 (a calcium and zinc chelator) and SK-PCB70M (a natural product) followed by 22 Phase II
compounds, RV-208 (a gene expression stimulator),
ARC-029 and ZSET-1446/ST-101 (calcium channel
blockers), CERE-110, GM-607, PYM-50058, and
T-817MA (trophic factor stimulators), circadin, KD501, PPL, PTX-200, resveratrol, RPh-201 (natural
products), LSL-001, N-251, PF-03049423, TRM189, VI-1121 (nootropics), davunetide, AM-111,
etanercept, and FGL (peptides).
CONCLUSION
DISCLOSURE STATEMENT
Two products were launched in 2012: tafamidis
(Vyndaquel, Pfizer) for the treatment of transthyretin
familial amyloid polyneuropathy in Europe in March
and 18 F-florbetapir (Amyvid; Avid Radiopharmaceuticals, Lilly) as a PET imaging agent to estimate
A␤ neuritic plaque density in patients with cognitive
impairment in the US in June.
Phase III Alzheimer’s disease trials of a disease
modifying drug, the monoclonal antibody against A␤
solanezumab (Lilly), are close to completion. First
results showed that solanezumab failed to meet the cognitive and functional primary endpoints. But it showed
a significant reduction in cognitive decline in patients
with mild AD. For a commentary, see [1695]. The
open-label EXPEDITION-EXT extension trial, which
is fully enrolled, is continuing as planned.
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1543).
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