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CINAPS COMPOUND DOSSIER
Triacetyluridine
10/22/2010
Table of Contents
I. Compound Information...................................................................................................... 3
II. Rationale.......................................................................................................................... 4
IIa. Scientific Rationale / Mechanism............................................................................... 4
IIb. Consistency............................................................................................................... 6
III. Efficacy (Animal Models of Parkinson’s Disease)........................................................... 7
IIIa. Animal Models: Rodent............................................................................................ 7
IIIb. Animal Models: Non-human Primates...................................................................... 7
IV. Efficacy (Clinical and Epidemiological Evidence)............................................................ 8
IVa. Clinical Studies......................................................................................................... 8
IVb. Epidemiological Evidence......................................................................................... 8
V. Relevance to Other Neurodegenerative Diseases........................................................... 9
VI. Pharmacokinetics........................................................................................................... 11
VIa. General ADME......................................................................................................... 11
VIb. CNS Penetration....................................................................................................... 11
VIc. Calculated log([brain]/[blood])................................................................................... 12
VII. Safety, Tolerability, and Drug Interaction Potential......................................................... 13
VIIa. Safety and Tolerability............................................................................................. 13
VIIb. Drug Interaction Potential........................................................................................ 13
VIII. Bibliography.................................................................................................................. 14
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I.
Compound Information
Common name: Triacetyluridine
Structure:
Pubchem ID: 20058
Mol. Formula: C15H18N2O9
FW: 370.31
CASRN: 4105-38-8
Polar surface area: 138
logP: -0.5
IUPAC name: [(2R,3R,4R,5R)-3,4-Diacetyloxy-5-(2,4-dioxopyrimidin-1-yl)-
oxolan-2-yl]methyl acetate
Other names: vistonuridine; uridine triacetate; TAU; PN401; RG2133
Drug class: Uridine pro-drug
Medicinal chemistry development potential: High
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II.
Rationale
IIa. Scientific Rationale / Mechanism
Uridine monophosphate (UMP) is synthesized de novo from glycine, and is successively
converted to uridine diphosphate (UDP) and uridine triphosphate (UTP). UTP can be converted to
cytidine triphosphate (CTP), and then to CDP-lipids and phosphatides key to the construction of
dendritic spines. Normal plasma and cerebrospinal fluid (CSF) levels of uridine in mammals are
3-8 µM. Administration of uridine or uridine equivalents such as the nutritional additive uridine
monophosphate (UMP) or the pro-drug triacetyluridine (TAU) at high dose levels are required to
attain levels that are in the range of 50-100 µM.1
Parkinson's Disease is characterized by (a) progressive degeneration of dopaminergic
nigrastatial neurons, (b) reduction in striatal dopamine, (c) reduction in dopaminergic synapses,
and (d) reduction in the density of dendritic spines on striatal medium spiny neurons. Uridine may
hold promise as a therapeutic intervention for (a) and (b).2
Electrophysiological Homeostasis, Effects on Phosphatides and Attendant Structural
Improvement in Neurites and Dendritic Spines
Uridine is crucial to the regulation of both normal physiological and pathological states. The
brain relies on a supply of circulating pyrimidines, namely uridine and cytidine, for
electrophysiological activity and for carbohydrate and phospholipid content. 1,
3-4
Uridine is a
precursor for brain CTP, the rate-limiting constituent in membrane phosphatide synthesis required
for neurite membranes.
UMP treatment increases striatal levels of cytoskeletal proteins (NF-70 and NF-M). These
structural proteins, which are highly enriched in neurites, have been demonstrated to be reliable
markers of neurite outgrowth. 5 Thus, their increases suggest increased branching or lengthening
of axons or dendrites. Longer or more branched neurites may increase the number of contacts
between the neurons and, consequently, the number of synapses that can be made between
them. Neurofilament proteins also maintain the structural integrity of neurons and participate in
intracellular axonal transport.6 These functions suggest their involvement in modulating
neurotransmitter release.
In addition to enhancing phosphatidyl choline synthesis via the Kennedy cycle, UTP promotes
neurite outgrowth by activating P2Y2 and other P2Y receptors. 2, 7 Activation of these G proteincoupled receptors can stimulate formation of downstream messengers, including IP3, DAG,
calcium, and protein kinase C, all of which can affect neurotransmitter release 8-9 and neurite
outgrowth.10
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Chronic administration of two circulating phosphatide precursors, UMP and the omega-3-fatty
acid docosahexaenoic acid (along with choline), to rats increases neuronal levels of the
phosphatides and of specific proteins that characterize synaptic membranes 11 as well as the
numbers of dendritic spines in brain. 12 In rat PC12 cells, exogenous uridine was shown to elevate
intracellular CDP-choline levels by promoting the synthesis of UTP, which was partly converted to
CTP. In such cells uridine also enhanced the neurite outgrowth produced by nerve growth factor
(NGF).13
Dopaminergic and Neuroprotective Activities
UMP supplementation increased the storage and release of striatal dopamine in aged rats. 13
Chronic treatment with uridine (15 mg/kg/day ip for 14 days) decreased binding of spiperone (a
D2 receptor antagonist) in the striatum of young rats, and increased the rate of recovery of striatal
spiperone-labeled dopamine receptors in young but not old rats in a process attributed to
modulation of the steady state and turnover of dopamine D2 receptors. 14 This uridine regimen
also decreased haloperidol-induced changes in striatal dopamine release. 15 Similar regimens in
two studies decreased amphetamine-induced increases in the release of striatal dopamine. 16
Thus, uridine may potentiate dopaminergic transmission when the levels of dopamine are
reduced, as is the case in parkinsonism. Uridine also caused the release of cholecystokinin,
which is stored in neurons and modulates dopamine receptors.1
UMP and TAU were protective in two neurotoxin models of Parkinson disease. In rats lesioned
with 6-hydroxydopamine, then challenged with methamphetamine, UMP (0.5% in diet for 3 days)
plus an omega-3-fatty acid decreased ipsilateral rotations by 57%, and increased tyrosine
hydroxylase and synapsin-1 protein levels, both indicative of a protective effect. 2 In MPTP-treated
mice, TAU (6% in the diet for 7 days) attenuated the depletion of striatal dopamine levels (84%
loss without TAU versus 71% with) and the loss of tyrosine hydroxylase-positive neurons in the
substantia nigra.17 MPTP-induced striatal dopamine loss and mortality were also attenuated in
another study using that treatment regimen with TAU.18
In two models of Huntington’s disease with polyglutamine repeats in the huntingtin protein and
abnormal folding (R6/2 and N171-82Q mice), TAU (6% in diet for 6 days) significantly decreased
huntingtin protein in the striatum and attenuated neurodegeneration in both piriform cortex and
striatum, while increasing brain-derived neurotrophic factor (BDNF) in the cortex. 19 BDNF
enhances hippocampal synaptic transmission by increasing NMDA receptor activity, and can be
an important mediator of neuroprotection and memory-enhancement. Similarly, TAU (6% in feed),
improved memory in an Alzheimer’s disease model, Tg2576(APPswe) mice, and motor
performance and survival in R6/2 and N171-82Q mice. In mice challenged with kainic acid, a rigid
analog of glutamate that induces hippocampal degeneration, TAU protected hippocampal
neurons and attenuated 3-nitropropionic acid-induced seizures in mice.18
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Mitochondrial and Bioenergetic Effects
The therapeutic effects of uridine and TAU have been linked to improvements in mitochondrial
function, as demonstrated by attenuation of the effects of specific toxicants of the electron
transport chain. The brain is particularly dependent on dihydroorotate dehydrogenase for
production of pyrimidines.20
Huntington’s disease is associated with decreased activity of mitochondrial succinate
dehydrogenase (complex II).21 De novo biosynthesis of uridine nucleotides is directly coupled to
the respiratory chain. Cells with impaired mitochondrial function become uridine auxotrophs and
can be maintained with high micromolar concentration of uridine and pyruvate. Provision of 4%
TAU in diet protected against 3-nitropropionic acid-induced neuronal damage in the striatum,
substantia nigra, decreased mortality and body weight loss, and improved performance on the
rotorod test.21 TAU also protected against azide-induced weight loss, mortality, and apoptosis in
the cerebral cortex.22
Antioxidant / Ischemia / ROS
Uridine may decrease the production of superoxide in brain by reducing dihydroorotate
oxidation.17 TAU decreases lipid peroxidation induced by LPS and ROS due to hydrogen peroxide
treatment of AD fibroblasts. 18 The early reports of Geiger and Yamazaki suggest that uridine
maintains brain metabolism during ischemia and hypoglycemia.23
Modulation of Nucleotide Metabolism by Uridine: Effect on CNS Disease States
High activity of purine 5-nucleotidase results in decreased salvage of uridine, and is related to
a form of autism with seizures. 24 Treatment with uridine improved seizures and behavior. Other
inherited disorders of pyrimidine metabolism that present with CNS dysfunction are UMP
synthase
deficiency25-26
and
the
dihydropyrimidine dehydrogenase,
1, 3-4
deficiencies of
steps
in
the
catabolic
pathway of
dihydropyrimidine amidohydrolase and beta-uridopropion-
ase. The authors speculate that these effects may be mediated through altered levels of uridine
25
and other pyrimidines.
IIb. Consistency
n/a
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III.
Efficacy (Animal Models of Parkinson’s Disease)
IIIa. Animal Models: Rodent
UMP and TAU were protective in two neurotoxin models of Parkinson's disease. In rats
lesioned with 6-hydroxydopamine, then challenged with methamphetamine, UMP (0.5% in diet for
3 days) plus an omega-3-fatty acid decreased ipsilateral rotations by 57%, and increased tyrosine
hydroxylase and synapsin-1 protein levels, both indicative of a protective effect. 2 In MPTP-treated
mice, TAU (6% in the diet for 7 days) attenuated the depletion of striatal dopamine levels (84%
loss without TAU versus 71% with) and the loss of tyrosine hydroxylase-positive neurons in the
substantia nigra.17 MPTP-induced striatal dopamine loss and mortality were also attenuated in
another study using that treatment regimen with TAU.18
Uridine has other potentially beneficial effects on CNS structure and function as noted
elsewhere (see Sections II and V).
IIIb. Animal Models: Non-human Primates
There were no reports of studies with TAU, uridine or its equivalents in nonhuman primates in
the literature.
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IV.
Efficacy (Clinical and Epidemiological Evidence)
IVa. Clinical Studies
No clinical studies of triacetyluridine were found in Parkinson's patients.
IVb. Epidemiological Evidence
n/a
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V.
Relevance to Other Neurodegenerative Diseases
TAU (6 g in repeated doses at 2-8 hour intervals) has been employed as a “rescue” agent for
the toxic effects of 5-fluorouracil in cancer studies. Plasma levels in the range associated with
CNS protective effects of uridine (50-100 µM) were achieved, 1,
27-28
and the drug was well-
tolerated.
Uridine decreased seizures in open trials for the treatment of epilepsy, 29 as well as in
treatment of children with a form of autism with seizures.24
Animal Models of Neurological Disease
In two models of Huntington’s disease with polyglutamine repeats in the huntingtin protein and
abnormal folding (R6/2 and N171-82Q mice), TAU (6% in diet for 6 days) significantly decreased
huntingtin protein in the striatum and attenuates neurodegeneration in both piriform cortex and
striatum.19
TAU (6% in feed), improved memory in an Alzheimer’s disease model, Tg2576(APPswe)
mice, and motor performance and survival in R6/2 and N171-82Q mice.18
TAU protected hippocampal neurons and attenuated 3-nitropropionic acid-induced seizures in
mice.18 Provision of 4% TAU in diet protected against 3-nitropropionic acid-induced neuronal
damage in the striatum, substantia nigra, decreased mortality and body weight loss, and
improved performance on the rotorod test. 21 TAU also protected against azide-induced weight
loss, mortality, and apoptosis in the cerebral cortex (cited by Klivenyi, et al., 200417).22
Structural Improvement
UMP treatment increases striatal levels of cytoskeletal proteins (NF-70 and NF-M) in rats.
These structural proteins, which are highly enriched in neurites, have been demonstrated to be
reliable markers of beneficial neurite outgrowth.13
Chronic administration of two circulating phosphatide precursors, UMP and the omega-3-fatty
acid docosahexanoic acid (along with choline), to rats increases neuronal levels of the
phosphatides and of specific proteins that characterize synaptic membranes 11 as well as the
numbers of dendritic spines in brain.12
Neurotransmission
Uridine increases the storage and release of striatal dopamine in rats.13 Chronic treatment with
uridine (15 mg/kg/day ip for 14 days) decreased spiperone binding in the striatum of young rats,
and increased the rate of recovery of striatal spiperone-labeled dopamine receptors in young but
not old rats in a process attributed to modulation of the steady state and turnover of dopamine D2
receptors.14 This uridine regimen also decreased haloperidol-induced changes in striatal
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dopamine release.15 Similar regimens in two studies decreased amphetamine-induced increases
in the release of striatal dopamine. 16 TAU (6% in the diet for 6 days) increased brain-derived
neurotrophic factor (BDNF) in the cortex.19 BDNF enhances hippocampal synaptic transmission
by increasing NMDA receptor activity, and can be an important mediator of neuroprotection and
memory-enhancement. In mice challenged with kainic acid, a rigid analog of glutamate that
induces hippocampal degeneration, TAU protected hippocampal neurons.18
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VI.
Pharmacokinetics
VIa. General ADME
While a therapeutic goal of treatment with uridine, UMP or TAU is to increase levels of uridine
in plasma, the efficacy of administration of uridine itself is limited by poor bioavailability and lower
tolerability due to osmotic diarrhea. 1 Therefore, the prodrug of uridine, triacetyluridine (TAU), was
commonly used in studies to achieve high, protective levels (50-100 µM) in plasma. TAU has
good bioavailability, and is readily cleaved to uridine by non-specific esterases. Uridine
monophosphate (UMP) was also used in studies in rat and human as a uridine equivalent that
can be delivered orally at high chronic doses, and produces high circulating levels of uridine.
Normal plasma levels of uridine range from 3-8 µM in plasma, and following intravenous
administration of high doses of uridine, uridine levels are rapidly restored to normal values. 1 After
1-h infusions of TAU (1-12 g/m2, roughly 300 mg/kg at the top dose) uridine levels decreased
with an initial half life of 40 min and a terminal half-life of 118 min, a volume of distribution of 634
mL/kg, and clearance of 5 ml/kg/min; each parameter was independent of dose.30
Provision of 6 g oral doses of TAU every 8 h achieved plasma uridine concentrations > 50 µM
in clinical studies,28 with similar plasma levels of uridine measured in another study employing 6 g
doses delivered each 6 h. An oral dose of UMP (2000 mg, approx 25 mg/kg) to patients raised
plasma uridine concentrations three-fold after 1-2 h.13
Erythrocytes serve another important role in uridine regulation. Unlike nucleated cells,
erythrocytes rapidly take up orotic acid and convert it to UDP-glucose. Erythrocyte stores of UDPglucose in brain and peripheral tissues are catabolized to provide both glucose and uridine, and
thus erythrocytes serve as a carrier and regulator of plasma levels of uridine.31
Uridine is actively transported across the gut by specific transporters. 1 In humans, these are
the hCNT1 and hCNT3 transporters. These specific nucleoside transporters traffic uridine into the
brain.17
Given the poor oral bioavailability of uridine, triacetyluridine (TAU) was developed as a
prodrug of the nucleoside. In contrast to uridine, TAU is well absorbed passively, and is cleaved
by nonspecific esterases to yield uridine in plasma. 17 Uridine is salvaged in mammals, but in also
excreted in urine, and accounts for the disposition of 24% of an intravenous dose.17
VIb. CNS Penetration
Uridine is maintained in the CSF at a concentration ranging from 3-8 µM, and enters the CSF
from the circulation and extracellular spaces. 1 Specific nucleoside transporters likely (hCNT1 and
hCNT3), traffic uridine into the brain.17
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VIc. Calculated log([brain]/[blood])
-1.98 (Clark Model32)
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VII.
Safety, Tolerability, and Drug Interaction Potential
VIIa.Safety and Tolerability
As an endogenous component in plasma, CSF and other biological matrices present in
micromolar concentrations, uridine presents little overt toxicity. However, at high oral doses
delivered with the aim of reaching levels (50-100 µM) that protect against the effects of 5fluorouracil, uridine causes osmotic diarrhea.33 The uridine prodrug, TAU, however, was described
as “well-tolerated” in the clinical literature reviewed even at repeated high oral dose levels that
produced protective levels of uridine in the circulation. 27-28 The only adverse effect experienced by
patients receiving intravenous infusion of nearly 20 g of uridine was shivering.30
VIIb.Drug Interaction Potential
No investigation of the interaction potential of uridine or its equivalents were found in the
literature, except for those demonstrating an amelioration of the toxicities of 5-fluorouracil when
coadministered with TAU.27-28, 30
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VIII.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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