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<br>[1]. Design, Synthesis, and Antiviral Activity of 2/’-Deoxy-2/’-fluoro-2/’-C-methyl-cytidine, a Potent Inhibitor of Hepatitis C Virus Replication By Clark, Jeremy L.; Hollecker, Laurent; Mason, J. Christian; Stuyver, Lieven J.; Tharnish, Phillip M.; Lostia, Stefa J. Med. Chem., 2005, 48 (17), pp 5504-5508
Abstract
The pyrimidine nucleoside beta-d-2/’-deoxy-2/’-fluoro-2/’-C-methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-d-arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-β-d-ribofuranosyl]cytosine (7a). The protected 2/’-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2/’-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2/’-C-methylcytidine and low cellular toxicity./
<br>[2]. Asif G, Hurwitz SJ, Shi J, Hernandez-Santiago BI, Schinazi RF. Pharmacokinetics of the antiviral agent beta-D-2/’-deoxy-2/’-fluoro-2/’-C-methylcytidine in rhesus monkeys. Antimicrob Agents Chemother. 2007 Aug;51(8):2877-82.
Abstract
beta-D-2/’-Deoxy-2/’-fluoro-2/’-C-methylcytidine (PSI-6130) is an effective inhibitor of hepatitis C virus (HCV) replication in vitro. The purpose of this study was to evaluate the single-dose pharmacokinetics of PSIota-6130 in rhesus monkeys following intravenous (i.v.) and oral administration. Noncompartmental analysis of the serum data obtained following oral and i.v. administration was performed. Pharmacokinetic studies with rhesus monkeys indicated slow and incomplete absorption with a mean absorption time (MAT) of 4.6 h and an oral bioavailability of 24.0% +/- 14.3% (mean +/- standard deviation), with comparable mean apparent half-lives following i.v. (4.54 +/- 3.98 h) and oral (5.64 +/- 1.13 h) administrations. The average percentages of the total dose recovered unchanged and in deaminated form in the urine were 32.9% +/- 12.6% and 18.9% +/- 6.6% (i.v.) and 6.0% +/- 3.9% and 3.9% +/- 1.0% (oral), respectively. The total bioavailability, taking into account the parent drug and its deaminated metabolite 2/’-deoxy-2/’-fluoro-2/’-C-methyluridine (PSI-6206), was 64% +/- 26%. PSI-6130 was present in the cerebrospinal fluid after oral and i.v. dosing. However, no deamination of radiolabeled PSI-6130 was detected after 8 h of incubation in monkey and human whole blood. An N(4)-modified prodrug of PSI-6130 (PSI-6419) was orally administered to monkeys, but it failed to improve the oral bioavailability of PSI-6130. Further studies are warranted to improve the oral bioavailability and reduce the deamination of PSI-6130 in order to explore the potential of this drug for the treatment of HCV-infected individuals.
<br>[3]. Murakami E, Niu C, Bao H, Micolochick Steuer HM, Whitaker T, Nachman T, Sofia MA, Wang P, Otto MJ, Furman PA. The mechanism of action of beta-D-2/’-deoxy-2/’-fluoro-2/’-C-methylcytidine involves a second metabolic pathway leading to beta-D-2/’-deoxy-2/’-fluoro-2/’-C-methyluridine 5/’-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Agents Chemother. 2008 Feb;52(2):458-64.
Abstract
beta-D-2/’-Deoxy-2/’-fluoro-2/’-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) RNA replication in an HCV replicon assay. The 5/’-triphosphate of PSI-6130 is a competitive inhibitor of the HCV RNA-dependent RNA polymerase (RdRp) and acts as a nonobligate chain terminator. Recently, it has been shown that the metabolism of PSI-6130 also results in the formation of the 5/’-triphosphate of the uridine congener, beta-D-2/’-deoxy-2/’-fluoro-2/’-C-methyluridine (PSI-6206; RO2433). Here we show that the formation of the 5/’-triphosphate of RO2433 (RO2433-TP) requires the deamination of PSI-6130 monophosphate and that RO2433 monophosphate is subsequently phosphorylated to the corresponding di- and triphosphates by cellular UMP-CMP kinase and nucleoside diphosphate kinase, respectively. RO2433-TP is a potent inhibitor of the HCV RdRp; however, both enzymatic and cell-based assays show that PSI-6130 triphosphate is a more potent inhibitor of the HCV RdRp than RO2433-TP.
<br>[4]. Ma H, Jiang WR, Robledo N, Leveque V, Ali S, Lara-Jaime T, Masjedizadeh M, Smith DB, Cammack N, Klumpp K, Symons J. Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2/’-Deoxy-2/’-fluoro-2/’-C-methylcytidine (PSI-6130) and identification of a novel active 5/’-triphosphate species. J Biol Chem. 2007 Oct 12;282(41):29812-20.
Abstract
beta-D-2/’-Deoxy-2/’-fluoro-2/’-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) replication in the subgenomic HCV replicon system, and its corresponding 5/’-triphosphate is a potent inhibitor of the HCV RNA polymerase in vitro. In this study the formation of PSI-6130-triphosphate was characterized in primary human hepatocytes. PSI-6130 and its 5/’-phosphorylated derivatives were identified, and the intracellular concentrations were determined. In addition, the deaminated derivative of PSI-6130, beta-d-2/’-deoxy-2/’-fluoro-2/’-C-methyluridine (RO2433, PSI-6026) and its corresponding phosphorylated metabolites were identified in human hepatocytes after incubation with PSI-6130. The formation of the 5/’-triphosphate (TP) of PSI-6130 (PSI-6130-TP) and RO2433 (RO2433-TP) increased with time and reached steady state levels at 48 h. The formation of both PSI-6130-TP and RO2433-TP demonstrated a linear relationship with the extracellular concentrations of PSI-6130 up to 100 mum, suggesting a high capacity of human hepatocytes to generate the two triphosphates. The mean half-lives of PSI-6130-TP and RO2433-TP were 4.7 and 38 h, respectively. RO2433-TP also inhibited RNA synthesis by the native HCV replicase isolated from HCV replicon cells and the recombinant HCV polymerase NS5B with potencies comparable with those of PSI-6130-TP. Incorporation of RO2433-5/’-monophosphate (MP) into nascent RNA by NS5B led to chain termination similar to that of PSI-6130-MP. These results demonstrate that PSI-6130 is metabolized to two pharmacologically active species in primary human hepatocytes.
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