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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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 2 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 3 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 4 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 5 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 6 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. CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 7 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 8 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 9 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 10 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 11 VIc. Calculated log([brain]/[blood]) -1.98 (Clark Model32) CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 12 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 CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 13 VIII. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Bibliography Connolly, G. P.; Duley, J. 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J., Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience 2005, 134 (1), 207-14. Krugel, U.; Kittner, H.; Franke, H.; Illes, P., Stimulation of P2 receptors in the ventral tegmental area enhances dopaminergic mechanisms in vivo. Neuropharmacology 2001, 40 (8), 1084-93. Shoji-Kasai, Y.; Itakura, M.; Kataoka, M.; Yamamori, S.; Takahashi, M., Protein kinase Cmediated translocation of secretory vesicles to plasma membrane and enhancement of neurotransmitter release from PC12 cells. Eur J Neurosci 2002, 15 (8), 1390-4. Sivasankaran, R.; Pei, J.; Wang, K. C.; Zhang, Y. P.; Shields, C. B.; Xu, X. M.; He, Z., PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat Neurosci 2004, 7 (3), 261-8. Wurtman, R. J.; Ulus, I. H.; Cansev, M.; Watkins, C. 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F.; Fuxe, K.; Ruggeri, M.; Merlo Pich, E.; Benfenati, F.; Volterra, V.; Ungerstedt, U.; Zini, I., Effects of chronic treatment with uridine on striatal dopamine release and dopamine related behaviours in the absence or the presence of chronic treatment with haloperidol. Neurochem Int 1989, 15 (1), 107-13. Myers, C. S.; Napolitano, M.; Fisher, H.; Wagner, G. C., Uridine and stimulant-induced motor activity. Proc Soc Exp Biol Med 1993, 204 (1), 49-53. Klivenyi, P.; Gardian, G.; Calingasan, N. Y.; Yang, L.; von Borstel, R.; Saydoff, J.; Browne, S. E.; Beal, M. F., Neuroprotective effects of oral administration of triacetyluridine against MPTP neurotoxicity. Neuromolecular Med 2004, 6 (2-3), 87-92. Joel, S.; Jin, G. S.; Zhongyi, H.; Alexis, G.; Liansheng, L.; Denise, B.; Rolando, A. G.; Sylvain, C.; Reid, W. v. B., PN401 decreases neurodegeneration in models of Alzheimer's, CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 14 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 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T.; von Borstel, R.; Bertino, J., Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer. J Clin Oncol 1997, 15 (4), 1511-7. Hidalgo, M.; Villalona-Calero, M. A.; Eckhardt, S. G.; Drengler, R. L.; Rodriguez, G.; Hammond, L. A.; Diab, S. G.; Weiss, G.; Garner, A. M.; Campbell, E.; Davidson, K.; Louie, A.; O'Neil, J. D.; von Borstel, R.; Von Hoff, D. D.; Rowinsky, E. K., Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies. J Clin Oncol 2000, 18 (1), 167-77. Bonavita, V.; Piccoli, F.; Savettieri, G.; Zito, M., [Observations on the therapeutic usefulness of uridine in epilepsy]. Acta Neurol (Napoli) 1975, 30 (1), 30-4. Leyva, A.; van Groeningen, C. J.; Kraal, I.; Gall, H.; Peters, G. J.; Lankelma, J.; Pinedo, H. M., Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5fluorouracil toxicity. Cancer Res 1984, 44 (12 Pt 1), 5928-33. Kong, W.; Engel, K.; Wang, J., Mammalian nucleoside transporters. Curr Drug Metab 2004, 5 (1), 63-84. Clark, D. E.; Pickett, S. D., Computational methods for the prediction of 'drug-likeness'. Drug Discov Today 2000, 5 (2), 49-58. Martin, D. S.; Stolfi, R. L.; Sawyer, R. C., Use of oral uridine as a substitute for parenteral uridine rescue of 5-fluorouracil therapy, with and without the uridine phosphorylase inhibitor 5-benzylacyclouridine. Cancer Chemother Pharmacol 1989, 24 (1), 9-14. CINAPS Dossier: Triacetyluridine 10/22/2010 PAGE 15