Structure-activity relationship (SAR) development and discovery of potent indole-based inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase

Journal of Medicinal Chemistry

Volumn 55, Issue 2, 2012, Pages 754-765

  Chen, Kevin X ^a   Vibulbhan, Bancha ^a   Yang, Weiying ^a   Sannigrahi, Mousumi ^a   Velazquez, Francisco ^a   Chan, Tin Yau ^a   Venkatraman, Srikanth ^a   Anilkumar, Gopinadhan N ^a   Zeng, Qingbei ^a   Bennet, Frank ^a   Jiang, Yueheng ^a   Lesburg, Charles A ^a   Duca, Jose ^a   Pinto, Patrick ^a   Gavalas, Stephen ^a   Huang, Yuhua ^a   Wu, Wanli ^a   Selyutin, Oleg ^a   Agrawal, Sony ^a   Feld, Boris ^a   Huang, Hsueh Cheng ^a   Li, Cheng ^a   Cheng, Kuo Chi ^a   Shih, Neng Yang ^a   Kozlowski, Joseph A ^a   Rosenblum, Stuart B ^b   Njoroge, F George ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b Merck Research Laboratories ^*

Author keywords

[No Author keywords available]

Indexed keywords

1 [(2 AMINO 4 PYRIDINYL)METHYL[ 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (TRIFLUOROMETHYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2 AMINO 4 PYRIDINYL)METHYL] 4 BROMO 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2 AMINO 4 PYRIDINYL)METHYL] 4,5 DICHLORO 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2 AMINO 4 PYRIDINYL)METHYL] 5 BROMO 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,4 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (TRIFLUOROMETHYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (1,1 DIMETHYLETHYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (METHOXY) 1H INDOLE CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (TRIFLUOROMETHOXY) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (TRIFLUOROMETHYL) 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHYL N (ETHYLSULFONYL) 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHYL N (METHYLSULFONYL) 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHYL N [(1 METHYLETHYL)SULFONYL] 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 METHYL 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 METHYL N [(1 METHYLETHYL)SULFONYL] 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 METHYL N METHYLSULFONYL) 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) N (ETHYLSULFONYL) 5 METHYL 1H INDOLE 2 CARBOXAMIDE; 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 [(1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHOXY] 1H INDOLE 2 CARBOXYLIC ACID; 1 [(2,6 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHYL 1H INDOLE 2 CARBOXYLIC ACID; 5 ACETYL 1 [(2 AMINO 4 PYRIDINYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 1H INDOLE 2 CARBOXYLIC ACID; 5 BROMO 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 1H INDOLE 2 CARBOXYLIC ACID; CARBOXYLIC ACID DERIVATIVE; INDOLE DERIVATIVE; N (CYCLOPROPYLSULFONYL) 1 [(2,5 DIFLUOROPHENYL(METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (1 METHYLCYCLOPROPYL) 1H INDOLE 2 CARBOXAMIDE; N (CYCLOPROPYLSULFONYL) 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (1,1 DIMETHYLETHYL) 1H INDOLE 2 CARBOXAMIDE; N (CYCLOPROPYLSULFONYL) 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 (TRIFLUOROMETHYL) 1H INDOLE 2 CARBOXAMIDE; N (CYCLOPROPYLSULFONYL) 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 ETHYL 1H INDOLE 2 CARBOXAMIDE; N (CYCLOPROPYLSULFONYL) 1 [(2,5 DIFLUOROPHENYL)METHYL] 3 (1,2 DIHYDRO 2 OXO 3 PYRIDINYL) 5 METHYL 1H INDOLE 2 CARBOXAMIDE; NONSTRUCTURAL PROTEIN 5B; RNA DIRECTED DNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DOG; DRUG POTENCY; DRUG STRUCTURE; HEPATITIS C VIRUS; IC 50; NONHUMAN; RAT; REPLICON; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTIVIRAL AGENTS; CACO-2 CELLS; CRYSTALLOGRAPHY, X-RAY; DOGS; HEPACIVIRUS; HUMANS; INDOLES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PERMEABILITY; RATS; REPLICON; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84863012084     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201258k     Document Type: Article

References (48)

1. Cohen, J. The Scientific Challenge of Hepatitis C Science 1999, 285, 26-30
2. Alter, M. J.; Kruszon-Moran, D.; Nainan, O. V.; McQuillan, G. M.; Gao, F.; Moyer, L. A.; Kaslow, R. A.; Margolis, H. S. The Prevalence of Hepatitis C Virus Infection in the United States, 1988 Through 1994 N. Engl. J. Med. 1999, 341, 556-562 (Pubitemid 29384163)
3. Cuthbert, J. A. Hepatitis C: Progress and Problems Clin. Microbiol. Rev. 1994, 7, 505-532 (Pubitemid 24317877)
4. Shepard, C. W.; Finelli, L.; Alter, M. J. Global epidemiology of hepatitis C virus infection Lancet Infect. Dis. 2005, 5, 558-567 (Pubitemid 41196755)
5. Monto, A.; Wright, T. L. The Epidemiology and Prevention of Hepatocellular Carcinoma Semin. Oncol. 2001, 28, 441-449 (Pubitemid 32959591)
6. Sheridan, C. New Merck and Vertex drugs raise standard of care in hepatitis C Nature Biotechnol. 2011, 29, 553-554
7. Fried, M. W.; Shiffman, M. L.; Reddy, D. K. R.; Smith, C.; Marinos, G.; Gonçales, F. L.; Häussinger, D.; Diago, M.; Carosi, G.; Dhumeaux, D.; Craxi, A.; Lin, A.; Hoffman, J.; Yu, J. PEGinterferon-α-2a plus ribavirin for chronic hepatitis C virus infection New Engl. J. Med. 2002, 347, 975-982
8. Di Bisceglie, A. M.; McHutchison, J.; Rice, C. M. New therapeutic strategies for hepatitis C Hepatology 2002, 35, 224-231 (Pubitemid 34032564)
9. Choo, Q. L.; Kuo, G.; Weiner, A. J.; 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 (Pubitemid 19117877)
10. Chen, K. X.; Njoroge, F. G. A review of HCV protease inhibitors Curr. Opin. Invest. Drugs 2009, 10, 821-837
11. Watkins, W. J.; Ray, A. S.; Chong, L. S. HCV NS5B polymerase inhibitors Curr. Opin. Drug Discovery Dev. 2010, 13, 441-465
12. Legrand-Abravanel, F.; Nicot, F.; Izopet, J. New NS5B polymerase inhibitors for hepatitis C Expert Opin. Invest. Drugs 2010, 19, 963-975
13. Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V..N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J.-H.; O'Boyle, D. R.; Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010, 465, 96-100
14. McHutchison, J. G.; Everson, G. T.; Gordon, S. C.; Jacobson, I. M.; Sulkowski, M.; Kauffman, R.; McNair, L.; Alam, J.; Muir, A. J.; Afdhal, N.; Arora, S.; Balan, V.; Vargas, H.; Bernstein, D.; Black, M.; Brown, R.; Bzowej, N.; Davis, G.; Di Bisceglie, A.; Dienstag, J.; Everson, G.; Faruqui, S.; Franco, J.; Fried, M.; Ghalib, R.; Gordon, S. C.; Gross, J.; Jacobson, I. M.; Jensen, D.; Kugelmas, M.; Kwo, P.; Lawitz, E.; Lee, W.; Martin, P.; Nelson, D.; Northup, P.; Patel, K.; Poordad, F.; Reddy, R. K.; Rodriguez-Torres, M.; Rustgi, V.; Schiff, E.; Sherman, K.; Shiffman, M.; Sulkowski, M.; Szabol, G.; Younossi, Z. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection N. Engl. J. Med. 2009, 360, 1827-1838
15. Kwo, P. Y.; Lawitz, E. J.; McCone, J.; Schiff, E. R.; Vierling, J. M.; Pound, D.; Davis, M. N.; Galati, J. S.; Gordon, S. C.; Ravendhran, N.; Rossaro, L.; Anderson, F. H.; Jacobson, I. M.; Rubin, R.; Koury, K.; Pedicone, L. D.; Brass, C. A.; Chaudhri, E.; Albrecht, J. K. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alpha-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial Lancet 2010, 376, 705-716
16. Perni, R. B.; Almquist, S. J.; Byrn, R. A.; Chandorkar, G.; Chaturvedi, P. R.; Courtney, L. F.; Decker, C. J.; Dinehart, K.; Gates, C. A.; Harbeson, S. L.; Heiser, A.; Kalkeri, G.; Kolaczkowski, E.; Lin, K.; Luong, Y.-P.; Rao, B. G.; Taylor, W. P.; Thomson, J. A.; Tung, R. D.; Wei, Y.; Kwong, A. D.; Lin, C. Preclinical profile of VX-950, a potent, selective, and orally, bioavailable inhibitor of hepatitis C virus NS3-4A serine protease Antimicrob. Agents Chemother. 2006, 50, 899-909 (Pubitemid 43327793)
17. Njoroge, F. G.; Chen, K. X.; Shih, N.-Y.; Piwinski, J. J. Challenges in Modern Drug Discovery: A Case Study of Boceprevir, an HCV Protease Inhibitor for the Treatment of Hepatitis C Virus Infection Acc. Chem. Res. 2008, 41, 50-59
18. Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu, Y.-T.; Lovey, R.; Hendrata, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.; Popov, V.; Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang, W.; Yang, W.; Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agarwal, S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.; Prongay, A.; Madison; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, T. Y.; Brisson, J.-M.; Prelusky, D.; Kormacher, W.; White, R.; Bogonowich-Knipp, S.; Pavlovsky, A.; Prudence, B.; Saksena, A. K.; Ganguly, A.; Piwinski, J.; Girijavallabhan, V.; Njoroge, F. G. Discovery of (1 R,5 S)- N -[3-Amino-1-(cyclobutylmethyl)-2-3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl) -amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable, hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection J. Med. Chem. 2006, 49, 6074-6086 (Pubitemid 44484951)
19. Behrens, S. E.; Tomei, L.; De Francesco, R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus EMBO J. 1996, 15, 12-22 (Pubitemid 26020384)
20. Lohmann, V.; Korner, F.; Herian, U.; Bartenschlager, R. Biochemical properties of hepatitis c virus ns5b RNAdependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity J. Virol. 1997, 71, 8416-8428 (Pubitemid 27446422)
21. Quinkert, D.; Bartenschlager, R.; Lohmann, V. Quantitative analysis of the hepatitis C virus replication complex J. Virol. 2005, 79, 13594-13605 (Pubitemid 41508172)
22. Lesburg, C. A.; Cable, M. B.; Ferrari, E.; Hong, Z.; Mannarino, A. F.; Weber, P. C. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site Nature Struct. Biol. 1999, 6, 937-943 (Pubitemid 29463307)
23. Ago, H.; Adachi, T.; Yoshida, A.; Yamamoto, M.; Habuka, N.; Yatsunami, K.; Miyano, M. Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus Structure 1999, 7, 1417-1426 (Pubitemid 29529882)
24. Liu, Y.; He, Y.; Molla, A. Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors. In: Antiviral Research: Strategies in Antiviral Drug Discovery; LaFemina, R. L., Ed.; ASM Press: Washington, DC, 2009; pp 137-151.
25. Beaulieu, P. L. Non-nucleoside inhibitors of the hcv ns5b polymerase: progress in the discovery and development of novel agents for the treatment of hcv infections Curr. Opin. Invest. Drugs 2007, 8, 614-634 (Pubitemid 47205246)
26. Watkins, W. J.; Ray, A. S.; Chong, L. S. HCV NS5B polymerase inhibitors Curr. Opin. Drug Discovery Dev. 2010, 13, 441-465
27. Legrand-Abravanel, F.; Nicot, F.; Izopet, J. New NS5B polymerase inhibitors for hepatitis C Expert Opin. Invest. Drugs 2010, 19, 963-975
28. Beaulieu, P. L. Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection Expert Opin. Ther. Pat. 2009, 19, 145-164
29. Ma, H.; Leveque, V.; De Witte, A.; Li, W.; Hendricks, T.; Clausen, S. M.; Cammack, N.; Klumpp, K. Inhibition of native hepatitis C virus replicase by nucleotide and non-nucleoside inhibitors Virology 2005, 332, 8-15 (Pubitemid 40127224)
30. 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 Nature Rev. Drug Discovery 2007, 6, 991-1000 (Pubitemid 350201789)
31. Pierra, C.; Amador, A.; Benzaria, S.; Cretton-Scott, E.; D'Amours, M.; Mao, J.; Mathieu, S.; Moussa, A.; Bridges, E. G.; Standring, D. M.; Sammadossi, J.-P.; Storer, R.; Gosselin, G. Synthesis and Pharmacokinetics of Valopicitabine (NM283), an Efficient Prodrug of the Potent Anti-HCV Agent 20-C-Methylcytidine J. Med. Chem. 2006, 49, 6614-6620 (Pubitemid 44657456)
32. (R1626) Smith, D. B.; Kalayanov, G.; Sund, G.; Winqvist, A.; Maltseva, T.; Leveque, V. J.-P.; Rajyagurr, S.; Le Pogam, S.; Najer, I.; Benkestock, K.; Zhou, X.-X.; Kaiser, A. C.; Maag, H.; Cammack, N.; Martin, J. A.; Swallow, S.; Johannsson, N. G.; Klumpp, K.; Smith, M. The Design, Synthesis, and Antiviral Activity of Monofluoro and Difluoro Analogues of 40-Axidocytidine against Hepatitis C Virus Replication: The Discovery of 40-Azido-20-deoxy-20- fluorocytidine and 40-Azido-20-dideoxy-20,20-difuorocytidine J. Med. Chem. 2009, 52, 2971-2978
33. (PSI-6130) Clark, J. L.; Hollecker, L.; Mason, J. C.; Stuyver, L. J.; Tharnish, P. M.; Lostia, S.; McBrayer, T. R.; Schinazi, R.; Watanabe, K. A.; Otto, M. J.; Furman, P. A.; Stec, W. J.; Patterson, S. E.; Pankiewicz, K. W. Design, Synthesis, and Antiviral Activity of 20-Deoxy-20-fluoro-20-C- methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication J. Med. Chem. 2005, 48, 5504-5508 (Pubitemid 41209247)
34. 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.; 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
35. Reddy, P. G.; Bao, D.; Chang, W.; Chun, B.-K.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Ross, B. S.; Zhang, H.-R.; Bansal, S.; Espiritu, C. L.; Keilman, M.; Lam, A. M.; Niu, C.; Steuer, H. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. 20-Deoxy-20-a-fluoro-20-b-C-methyl 30,50-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938 Bioorg. Med. Chem. Lett. 2010, 20, 7376-7380
36. Cretton-Scott, E.; Perigaud, C.; Peyrottes, S.; Licklider, L.; Camire, M.; Larsson, M.; La Colla, M.; Hildebrand, E.; Lallos, L.; Bilello, J.; McCarville, J.; Seifer, M.; Liuzzi, M.; Pierra, C.; Badaroux, E.; Gosselin, G.; Surleraux, D.; Standring, D. N. In vitro antiviral activity and pharmacology of IDX184, a novel and potent inhibitor of HCV replication J. Hepatol. 2008, 48, S220-S225
37. McGuigan, C.; Madela, K.; Aljarah, M.; Gilles, A.; Brancale, A.; Zonta, N.; Chamberlain, S.; Vernachio, J.; Hutchins, J.; Hall, A.; Ames, B.; Gorovits, E.; Ganguly, B.; Kolykhalov, A.; Wang, J.; Muhammadb, J.; Patti, J. M.; Henson, G. Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus Bioorg. Med. Chem. Lett. 2010, 20, 4850-4854
38. Kneteman, N. M.; Howe, A. Y.; Gao, T.; Lewis, J.; Pevear, D.; Lund, G.; Douglas, D.; Mercer, D. F.; Tyrrell, D. L.; Immermann, F.; Chaudhary, I.; Speth, J.; Villano, S. A.; O'Connell, J.; Collett, M. HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus Hepatology 2009, 49, 745-752
39. Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Jewell, T.; Patel, L.; Ludlum, S.; Drowns, M.; Rahavendran, S. V.; Skor, H.; Hunter, R.; Shi, S. T.; Herlihy, K. J.; Parge, H.; Hickey, M.; Yu, X.; Chau, F.; Nonomiya, J.; Lewis, C. Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- dimethyl-[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydro- pyran-2-one (PF-00868554) as a Potent and Orally Available Hepatitis C Virus Polymerase Inhibitor J. Med. Chem. 2009, 52, 1255-1258
40. Rodriguez-Torres, M.; Lawitz, E.; Conway, B.; Kaita, K.; Sheikh, A. M.; Ghalib, R.; Adrover, R.; Cooper, C.; Silva, M.; Rosario, M.; Bourgault, B.; Proulx, L.; McHutchison, J. G. Safety and antiviral activity of the non-nucleoside polymerase inhibitor VX-222 in treatment naïve genotype 1 HCV infected patients J. Hepatol. 2010, 52, S14-S18
41. Lawitz, E.; Rodrigues-Torres, M.; DeMicco, T.; Nguyen, T.; Godofsky, E.; Appleman, J.; Rahimy, M.; Crowley, C.; Freddo, J. Antiviral activity of ANA598, a potent non-nucleoside polymerase inhibitor, in chronic hepatitis C patients J. Hepatol. 2009, 50, S384-S387
42. Larrey, D.; Benhamou, Y.; Lohse, A. W.; Trepo, C.; Moelleken, C.; Bronowicki, J.-P.; Heim, M. H.; Arastéh, K.; Zarski, J.-P.; Bourlière, M.; Wiest, R.; Calleja, J. L.; Enríquez, J.; Erhardt, A.; Wedemeyer, H.; Gerlach, T.; Berg, T.; Stern, J. O.; Wu, K.; Abdallah, N.; Nehmiz, G.; Boecher, W. O.; Berger, F. M.; Steffgen, J. BI 207127 is a potent HCV RNA polymerase inhibitor during 5 days monotherapy in patients with chronic hepatitis C Hepatology 2009, 50, 1044A-1046A
43. BMS-791325 from Bristol-Myers Squibb Has Been Advanced to Phase II Clinical Trials; http://clinicaltrials.gov/ct2/show/NCT01193361?term=bms- 791325&rank=4 (Accessed January 5, 2012).
44. Ferrari, E.; He, Z.; Palermo, R. E.; Huang, H. C. Hepatitis C Virus NS5B Polymerase Exhibits Distinct Nucleotide Requirements for Initiation and Elongation J. Biol. Chem. 2008, 283, 33893-33901
45. Lohmann, V.; Körner, F.; Koch, J.-O.; Herian, U.; Theilmann, L.; Bartenschlager, R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line Science 1999, 285, 110-113 (Pubitemid 29307577)
46. Anilkumar, G. N.; Lesburg, C. A.; Selyutin, O.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Chan, T.-Y.; Pu, H.; Vaccaro, H.; Wang, L.; Bennett, F.; Chen, K. X.; Duca, J.; Gavalas, S.; Huang, Y.; Pinto, P.; Sannigrahi, M.; Velazquez, F.; Venkatraman, S.; Vibulbhan, B.; Agrawal, S.; Butkiewicz, N.; Feld, B.; Ferrari, E.; He, Z.; Jiang, C.-K.; Palermo, R. E.; Mcmonagle, P.; Huang, H.-C.; Shih, N.-Y.; Njoroge, G.; Kozlowski, J. A. I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acids with C-3-Heterocycles Bioorg. Med. Chem. Lett. 2011, 21, 5336-5341
47. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloarenes: A Direct Procedure for Arylboronic Esters J. Org. Chem. 1995, 60, 7508-7510
48. Jansen, M.; Dannhardt, G. Variations of acidic functions at position 2 and substituents at positions 4, 5 and 6 of the indole moiety and their effect on NMDA-glycine site affinity Eur. J. Med. Chem. 2003, 38, 855-865 (Pubitemid 37314019)