A 2′-deoxy-2′-fluoro-2′-C-methyl uridine cyclopentyl carbocyclic analog and its phosphoramidate prodrug as inhibitors of HCV NS5B polymerase

Nucleosides, Nucleotides and Nucleic Acids

Volumn 31, Issue 4, 2012, Pages 277-285

  Liu, Jian ^a   Du, Jinfa ^a   Wang, Peiyuan ^a   Nagarathnam, Dhanapalan ^a   Espiritu, Christine L ^a   Bao, Haiying ^a   Murakami, Eisuke ^a   Furman, Phillip A ^a   Sofia, Michael J ^a  

^a PHARMASSET INC   (United States)

Author keywords

2 Deoxy 2 fluoro 2 C methyluridine nucleotide; cyclopentyl carbocyclic uridine nucleoside; hepatitis C virus; phosphoramidate prodrug; PSI 7851; PSI 7977

Indexed keywords

1 [2 FLUORO 3 HYDROXY 4 (HYDROXYMETHYL) 2 METHYLCYCLOPENTYL]PYRIMIDINE 2,4 (1H,3H)DIONE; ANTIVIRUS AGENT; CARBOCYCLIC NUCLEOSIDE; ISOPROPYL 2 [[[[4 (2,4 DIOXO 3,4 DIHYDROPYRIMIDIN 1 (2H)YL) 3 FLUORO 2 HYDROXY 3 METHYLCYCLOPENTYL]METHOXY](PHENOXY)PHOSPHORYL]AMINO]PROPANOATE; NONSTRUCTURAL PROTEIN 5B; PHOSPHORAMIDIC ACID DERIVATIVE; PRODRUG; PSI 7851; PSI 7977; UNCLASSIFIED DRUG; 1 (2 FLUORO 3 HYDROXY 4 (HYDROXYMETHYL) 2 METHYLCYCLOPENTYL)PYRIMIDINE 2,4(1H,3H) DIONE; 1-(2-FLUORO-3-HYDROXY-4-(HYDROXYMETHYL)-2-METHYLCYCLOPENTYL)PYRIMIDINE-2,4(1H,3H)-DIONE; CYCLOPENTANE DERIVATIVE; DEOXYURIDINE; DRUG DERIVATIVE; ISOPROPYL 2 ((((4 (2,4 DIOXO 3,4 DIHYDROPYRIMIDIN 1(2H) YL) 3 FLUORO 2 HYDROXY 3 METHYLCYCLOPENTYL)METHOXY)(PHENOXY)PHOSPHORYL)AMINO)PROPANOATE; ISOPROPYL 2-((((4-(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-1(2H)-YL)-3-FLUORO-2-HYDROXY-3-METHYLCYCLOPENTYL)METHOXY)(PHENOXY)PHOSPHORYL)AMINO)PROPANOATE; NS 5 PROTEIN, HEPATITIS C VIRUS; NS-5 PROTEIN, HEPATITIS C VIRUS; ORGANOPHOSPHORUS COMPOUND; VIRUS PROTEIN;

ANTIVIRAL ACTIVITY; ARTICLE; DIASTEREOISOMER; DRUG SYNTHESIS; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; NONHUMAN; STRUCTURE ACTIVITY RELATION; VIRUS REPLICATION; CELL LINE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; SYNTHESIS;

HEPATITIS C VIRUS;

ANTIVIRAL AGENTS; CELL LINE; CYCLOPENTANES; DEOXYURIDINE; HEPACIVIRUS; HUMANS; ORGANOPHOSPHORUS COMPOUNDS; PRODRUGS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84859203767     PISSN: 15257770     EISSN: 15322335     Source Type: Journal    
DOI: 10.1080/15257770.2012.658131     Document Type: Article

References (14)

1. Choo, Q.L.; Kuo, G.; Weiner, A.J.; Overby, L.R.; Bradley, D.W.; Houghton, M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989, 244, 359-362.
2. Hepatitis C; World Health Organization Fact Sheet No. 164, World Health Organization, Geneva, October 2000.
3. Lavanchy, D. The global burden of hepatitis C. Liver Int. 2009, 29(S1), 74.
4. Manns, M.P.; Foster, G.R.; Rockstroh, J.K.; Zeuzem, S.; Zoulim, F.; Houghton, M. The way forward in HCV treatment-finding the right path. Nat. Rev./Drug Discov. 2007, 6, 991-1000.
5. Kwong, A.D.; McNair, L.; Jacobson, I.; George, S. Recent progress in the development of selected hepatitis C virus NS3.4A protease and NS5B polymerase inhibitors. Curr. Opin. Pharmacol. 2008, 8, 522-531.
6. Lemm, J.A.; O'Boyle II, D.; Liu, M.; Nower, P.T.; Colonno, R.; Deshpande, M.S.; Snyder, L.B.; Martin, S.W.; St. Laurent, D.R.; Serrano-Wu, M.H.; Romine, J.L.; Meanwell, N.A.; Gao, M. Identification of hepatitis C virus NS5A inhibitors. J. Virol. 2010, 84, 482-491.
7. Sofia, M.J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P.G.; Ross, B.S.; Wang, P.; Zhang, H-R; Bansal, S.; Espiritu, C; Keilman, M.; Lam, A.M.; Steuer, H.M.M.; Niu, C; Otto, M.J.; Furman, P.A. Discovery of a β-D-2′-deoxy-2′-α-fluoro-2′-β- C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 7202-7218.
8. (a) Mieczkowski, A.; Agrofoglio, L.A. Synthesis and biological activity of selected carbocyclic nucleosides, in Modified Nucleosides in Biochemistry, Biotechnology and Medicine, ed. P. Herdewijn, Wiley-VCH, Weinheim, 2008, pp. 393-424;
9. (b) Chu, C.K. Antiviral Nucleosides: Chiral Synthesis and Chemotherapy, Elsevier B.V., Amsterdam, 2003, pp. 130-146;
10. (c) Crimmins, M.T. New developments in the enantioselective synthesis of cyclopentyl carbocyclic nucleosides. Tetrahedron 1998, 54, 9229-9272.
11. Santana, L.; Teijeira, M.; Uriarte, E. A slightly shorter route to carbocyclic nucleosides. Synthesis of (+/-)-trans-1-[2-(hydroxymethyl) cyclopentylmethyl]uracil. J. Heterocyclic Chem. 1999, 36, 293-295.
12. Clark, J.L.; Hollecker, L.; Mason, J.C.; Stuyver, L.J.; Tharnish, P.M.; Lostia, S.; McBrayer, T.R.; Schinazi, R.F.; Watanabe, K.A.; Otto, M.J.; Furman, P.A.; Stec, W.J.; Patterson, S.E.; Pankiewicz, K.W. Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J. Med. Chem. 2005, 48, 5504-5508.
13. Hayakawa, H.; Tanaka, H.; Itoh, N.; Nakajima, M.; Miyasaka, T.; Yamaguchi, K.; Iitaka, Y. Reaction of organometallic reagents with 2′- and 3′-ketouridine derivatives: synthesis of uracil nucleosides branched at the 2′- and 3′- positions. Chem. Pharm. Bull. 1987, 35(6), 2605-2608.
14. Saenger, W. Principles of Nucleic Acid Structure, Springer-Verlag, New York, Berlin, Heilderberg, 1984, pp. 9-28.