Quinolones as HCV NS5B polymerase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 1, 2011, Pages 82-87

  Kumar, Dange V ^a   Rai, Roopa ^b   Brameld, Ken A ^c   Somoza, John R ^d   Rajagopalan, Ravi ^e   Janc, James W ^f   Xia, Yu M ^g   Ton, Tony L ^h   Shaghafi, Michael B ⁱ   Hu, Huiyong ^j   Lehoux, Isabelle ^k   To, Nhat ^l   Young, Wendy B ^j   Green, Michael J ^m  

^a Myriad Pharmaceuticals   (United States)

^b AliosBiopharma   (United States)

^c Drug by Design   (United States)

^d GILEAD SCIENCES   (United States)

^e InterMune Inc   (United States)

^f THERAVANCE INC   (United States)

^g Crown Bioscience   (China)

^h 3399 Lake Arrowhead Ave ^*  (United States)

ⁱ UNIVERSITY OF CALIFORNIA   (United States)

^j GENENTECH INC   (United States)

^k Allosteros Therapeutics   (United States)

^l UNIVERSITY OF CALIFORNIA   (United States)

^m Virobay Inc   (United States)

more..

Author keywords

Cocrystal structure; HCV; HCV NS5B NNI 2 binder; Non nucleoside inhibitors; NS5B polymerase inhibitors; Quinolone derivatives

Indexed keywords

FILIBUVIR; GSK 625433; JTK 109; NESBUVIR; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; NONSTRUCTURAL PROTEIN 5B; QUINOLONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CRYSTAL STRUCTURE; HEPATITIS C VIRUS; LIFE CYCLE; NONHUMAN; SITE DIRECTED MUTAGENESIS; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION;

ALLOSTERIC REGULATION; ANTIVIRAL AGENTS; BINDING SITES; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HEPACIVIRUS; QUINOLONES; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 78650513766     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.11.068     Document Type: Article

References (23)

1. Q.L. Choo, K.H. Richman, J.H. Han, K. Berger, C. Lee, C. Dong, C. Gallegos, D. Coit, R. Medina-Selby, and P.J. Barr Proc. Natl. Acad. Sci. U.S.A. 88 1991 2451
2. J. Cohen Science 285 1999 26
3. K.E. Reed, and C.M. Rice Curr. Top. Microbiol. Immunol. 242 2000 55
4. J.G. McHutchison Am. J. Manag. Care 10 2004 S21
5. L.B. Seeff Semin Gastrointest. Dis. 6 1995 20
6. M.W. Fried, M.L. Shiffman, K.R. Reddy, C. Smith, G. Marinos, F.L. Goncales Jr., D. Haussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffman, and J. Yu N. Eng. J. Med. 347 2002 975
7. N. Hayashi, and T. Takehara J. Gastroenterol. 41 2006 17
8. M.P. Manns, J.G. McHutchison, S.C. Gordon, V.K. Rustgi, M. Shiffman, R. Reindollar, Z.D. Goodman, K. Koury, M. Ling, and J.K. Albrecht Lancet 358 2001 958
9. M.P. Manns, G.R. Foster, J.K. Rockstroh, S. Zeuzem, F. Zoulim, and M. Houghton Nat. Rev. Drug Disc. 6 2007 991
10. A.A. Kolykhalov, K. Mihalik, S.M. Feinstone, and C.M. Rice J. Virol. 74 2000 2046
11. A. Erhardt, K. Deterding, Y. Benhamou, M. Reiser, X. Forns, S. Pol, J.L. Calleja, S. Ross, H.C. Spangenberg, J. Garcia-Samaniego, M. Fuchs, J. Enriquez, J. Wiegand, J. Stern, K. Wu, G. Kukolj, M. Marquis, P. Beaulieu, G. Nehmiz, and J. Steffgen Antivir. Ther. 14 2009 23
12. N.M. Kneteman, A.Y. Howe, T. Gao, J. Lewis, D. Pevear, G. Lund, D. Douglas, D.F. Mercer, D.L. Tyrrell, F. Immermann, I. Chaudhary, J. Speth, S.A. Villano, J. O'Connell, and M. Collett Hepatology 49 2009 745
13. P. Toniutto, C. Fabris, D. Bitetto, E. Fumolo, E. Fornasiere, and M. Pirisi IDrugs 11 2008 738
14. J.Q. Hang, Y. Yang, S.F. Harris, V. Leveque, H.J. Whittington, S. Rajyaguru, G. Ao-Ieong, M.F. McCown, A. Wong, A.M. Giannetti, S. Le Pogam, F. Talamas, N. Cammack, I. Najera, and K. Klumpp J. Biol. Chem. 284 2009 15517
15. U. Koch, and F. Narjes Infect. Disord. Drug Targets 6 2006 31
16. F. Pauwels, W. Mostmans, L.M. Quirynen, L. van der Helm, C.W. Boutton, A.S. Rueff, E. Cleiren, P. Raboisson, D. Surleraux, O. Nyanguile, and K.A. Simmen J. Virol. 81 2007 6909
17. V. Lohmann, F. Korner, J.-O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager Science 285 1999 110
18. 12) and 0.8 μg/ml poly(rA) to assay wells containing enzyme preincubated with inhibitor. Reactions were terminated after 120 min by the addition of 20 μl of stop solution containing 150 μg/ml tRNA and 10 mg/ml streptavidin-coated SPA beads (Amersham) in 20 mM Tris-HCl pH 7.5, 25 mM KCl, 0.5 M EDTA and 0.025% sodium azide. After incubation for 30 min, 65 μl of 5 M cesium chloride were added to the wells and further incubated for 1 h before top-counting in a Microbeta Trilux plate reader.
19. 50's were calculated using a standard 4 parameter curve fit model.
20. Kumar, D. V.; Rai, R. WO 2007/005779, 2007.
21. M. Wang, K.K. Ng, M.M. Cherney, L. Chan, C.G. Yannopoulos, J. Bedard, N. Morin, N. Nguyen-Ba, M.H. Alaoui-Ismaili, R.C. Bethell, and M.N. James J. Biol. Chem. 278 2003 9489
22. R.A. Love, H.E. Parge, X. Yu, M.J. Hickey, W. Diehl, J. Gao, H. Wriggers, A. Ekker, L. Wang, J.A. Thomson, P.S. Dragovich, and S.A. Fuhrman J. Virol. 77 2003 7575
23. 3 (3 equiv) to afford compound 3 in 70% yield.