Discovery of proline sulfonamides as potent and selective hepatitis C virus NS5b polymerase inhibitors. Evidence for a new NS5b polymerase binding site

Journal of Medicinal Chemistry

Volumn 49, Issue 11, 2006, Pages 3052-3055

  Gopalsamy, Ariamala ^a   Chopra, Rajiv ^a   Lim, Kitae ^a   Ciszewski, Gregory ^a   Shi, Mengxiao ^a   Curran, Kevin J ^a   Sukits, Steven F ^a   Svenson, Kristine ^a   Bard, Joel ^a   Ellingboe, John W ^a   Agarwal, Atul ^a   Krishnamurthy, Girija ^a   Howe, Anita Y M ^a   Orlowski, Mark ^a   Feld, Boris ^a   O'Connell, John ^a   Mansour, Tarek S ^a  

^a WYETH RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HEPATITIS C VIRUS NS5B POLYMERASE INHIBITOR; PROLINE DERIVATIVE; PROLINE SULFONAMIDE DERIVATIVE; RNA DEPENDENT RNA POLYMERASE INHIBITOR; RNA DIRECTED RNA POLYMERASE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BINDING SITE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG SELECTIVITY; ENZYME ACTIVE SITE; HEPATITIS C VIRUS; HIGH THROUGHPUT SCREENING; IC 50; MOLECULAR MODEL; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANTIVIRAL AGENTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROLINE; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; VIRAL NONSTRUCTURAL PROTEINS;

EID: 33744808547     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060168g     Document Type: Article

References (18)

1. (a) Alter, M. J. D.; Kruszon-Moran, O. V.; Nainan, G. M.; McQuillan, F.; Gao, L. A.; Moyer, R. A.; Kaslow, ; H. S. Margolis. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. New Engl. J. Med. 1999, 341, 556-562.
2. (b) Cohen, J. The Scientific Challenge of Hepatitis C. Science 1999, 285, 26-30.
3. (c) Memom, M. I.; Memom, M. A. Hepatitis C: An Epidemilogical Review. J. Viral Hepatitis 2002, 9, 84-100.
4. (d) Hanazaki, K. Current Antiviral Therapy for Chronic Hepatitis C Including Liver Transplantation and Hepatic Resection, Curr. Med. Chem. Anti-infective Agents 2003, 2, 103-111.
5. Manns, M. P., J. G.; McHutchison, S. C.; Gordon, V. K.; Rustgi, M.; Shiffman, R.; Reindollar, Z. D.; Goodman, K.; Koury, M.; Ling.; Albrecht, J. K. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001, 358, 958-965.
6. Beaulieu, P. L.; Montse, L.-B. Therapies for hepatitis C infection: targeting the non-structural proteins of HCV. Curr. Med. Chem. Anti-Infective Agents 2002, 1, 163-176.
7. (a) Thibeault, D.; Bousquet, C.; Gingras, R.; Lagace, L.; Maurice, R.; White, P. W.; Lamarre, D. Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061 J. Viral. 2004, 78, 7352-7359.
8. (b) Lamarre, D.; Anderson, P. C. Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Boes, M. Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A. Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M.; Rancourt, J.; Sentjens, R. E.; St. George R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S. Weldon, S. M.; Yong, C.; Llinas-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003, 426, 186-189.
9. (a) Gopalsamy, A.; Lim, K.; Ciszewski, G.; Park, K.; Ellingboe, J. W.; Bloom, J.; Insaf, S.; Upeslacis, J.; Mansour, T. S.; Krishnamurthy, G.; Damarla, M.; Pyatski, Y.; Ho, D.; Howe, A. Y. M.; Orlowski, M.; Feld, B.; O'Connell, J. Discovery of Pyrano[3,4-b]indoles as potent and selective HCV NS5b polymerase inhibitors. J. Med. Chem. 2004, 47, 6603-6608.
10. (b) Howe, A. Y. M.; Bloom, J.; Baldick, C. J.; Benetatos, C. A.; Cheng, H.; Christensen, J. S.; Chunduru, S. K.; Coburn, G. A.; Feld, B.; Gopalsamy, A.; Gorczyca, W. P.; Herrmann, S.; Johann, S.; Jiang, X.; Kimberland, M. L.; Krisnamurthy, G.; Olson, M.; Orlowski, M.; Swanberg, S.; Thompson, I.; Thorn, M.; Del Vecchio, A.; Young, D. C.; van Zeijl, M.; Ellingboe, J. W.; Upeslacis, J.; Collett, M.; Mansour, T. S.; O'Connell, J. F. Novel nonnucleoside inhibitor of hepatitis C virus RNA-dependent RNA polymerase. Antimicrob. Agents Chemother. 2004, 48, 4813-4821.
11. (a) Summa, V.; Petrocchi, A.; Pace, P.; Matassa, V. G.; De Francesco, R.; Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. Discovery of a, γ -Diketo Acids as Potent Selective and Reversible Inhibitors of Hepatitis C Virus NS5b RNA-Dependent RNA Polymerase. J. Med. Chem. 2004, 47, 14-17.
12. (b) Wang, M.; Ng, K. K.-S.; Cherney, M. M.; Chan, L.; Yannopoulos, C. G.; Bedard, J.; Morin, N.; Nguyen-Ba, N.; Alaoui-Ismaili, M. H.; Bethell, R. C.; James, M. N. G. Non-nucleoside Analogue Inhibitors Bind to an Allosteric Site on HCV NS5b Polymerase. J. Biol. Chem. 2003, 278, 9489-9495.
13. (c) Chan, L.; Bedard, J.; Das, S. K.; Nguyen-Ba, N.; Pereira, O. Z.; Reddy, T. J.; Siddiqui, M. A.; Wang, W.; Yannopoulos, C. WO 2002100851, 2002.
14. (d) Love, R. A.; Parge, H. E.; Yu, X.; Hickey, M. J.; Diehl, W.; Gao, J.; Wriggers, H.; Ekker, A.; Wang, L.; Thomson, J. A.; Dragovich, P. S.; Fuhrman, S. A. Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5b RNA polymerase enzyme. J. Virol. 2003, 77, 7575-7581.
15. (e) Condon, S. M.; LaPorte, M. G.; Herberb, T. Allosteric inhibitors of hepatitis C NS5B RNA-dependent RNA polymerase. Curr. Med. Chem. Anti-Infective Agents 2005, 4, 99-110.
16. (f) Harper, S.; Avolio, S.; Pacini, B.; Di Filippo, M.; Altamura, S.; Tomei, L.; Paonessa, G.; Di Marco, S.; Carfi, A.; Giuliano, C.; Padron, J.; Bonelli, F.; Migliaceio, G.; De Francesco, R.; Lauter, R.; Rowley, M.; Narjes, F. Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase. J. Med. Chem. 2005, 48, 4547-4557.
17. (g) Gordon, C. P.; Keller, P. A. Control of Hepatitis C: A Medicinal Chemistry Perspective. J. Med. Chem. 2005, 48, 1-20.
18. Internal energies were calculated by using MMFF94 force field in Sybyl 7.0 of Tripos. Inc. 1699 South Hanley Rd., St. Louis, MO 63144-2913.