Depeptidization efforts on P3-P′2 α-ketoamide inhibitors of HCV NS3-4A serine protease: Effect on HCV replicon activity

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 6, 2006, Pages 1621-1627

  Bogen, Stéphane L ^a   Ruan, Sumei ^a   Liu, Rong ^a   Agrawal, Sony ^a   Pichardo, John ^a   Prongay, Andrew ^a   Baroudy, Bahige ^a   Saksena, Anil K ^a   Girijavallabhan, Viyyoor ^a   Njoroge, F George ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; CARBOXYLIC ACID; NITROGEN; NONSTRUCTURAL PROTEIN 3; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; NS3 PROTEIN, HEPATITIS C VIRUS; VIRUS PROTEIN;

ARTICLE; DRUG SYNTHESIS; HEPATITIS C VIRUS; METHYLATION; NONHUMAN; OXIDATION; REPLICON; VIRUS INHIBITION; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; PROTEIN BINDING; STRUCTURE ACTIVITY RELATION; SYNTHESIS; X RAY DIFFRACTION;

HEPATITIS C VIRUS;

AMIDES; BINDING SITES; HEPACIVIRUS; METHYLATION; MOLECULAR STRUCTURE; NITROGEN; PROTEIN BINDING; REPLICON; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; X-RAY DIFFRACTION;

EID: 32044463311     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.12.013     Document Type: Article

References (34)

1. Consensus Panel. EASL International Consensus Conference on Hepatitis C, Paris, February 26-28, 1999, Consensus Statement J. Hepatol. 30 1999 956
2. J. Cohen Science 285 1999 26
3. M. Houghten B.N. Fields D.M. Knipe P.M. Howley Virology 1996 Raven Press New York 1035 1058
4. J.A. Cuthbert Clin. Microbiol. Rev. 7 1994 505
5. B.W. Dymock Emerg. Drugs 6 2001 13 and references cited therein
6. A.A. Kolykhalov, K. Mihalik, S.M. Feinstone, and C.M. Rice J. Virol. 74 2000 2046
7. R. Bartenschlager, and V. Lohmann J. Gen. Virol. 81 2000 1631
8. R. De Francesco, L. Tomei, S. Altamura, V. Summa, and G. Migliaccio Antiviral Res. 58 2003 1
9. C. Steinkuhler, U. Koch, F. Narjes, and V.G. Matassa Curr. Med. Chem. 8 2001 919
10. A.D. Kwong, J.L. Kim, G. Rao, D. Lipovsek, and S.A. Raybuck Antiviral Res. 40 1998 1
11. A. Arasappan, F.G. Njoroge, T.Y. Chan, F. Bennett, S. Bogen, K. Chen, H. Gu, L. Hong, E. Jao, Y.-T. Liu, R.G. Lovey, T. Parekh, R.E. Pike, P. Pinto, S. Santhanam, V. Venkatraman, H. Vaccaro, H. Wang, X. Yang, B. Zhu, B. Mckittrick, A.K. Saksena, V. Girijavallabhan, J. Pichardo, N. Butkiewicz, R. Ingram, B. Malcolm, A. Prongay, N. Yao, B. Marten, V. Madison, S. Kemp, O. Levy, M. Lim-Wilby, S. Tamura, and A.K. Ganguly Bioorg. Med. Chem. Lett. 15 2005 4180
12. A. Arasappan, F.G. Njoroge, T.N. Parekh, X. Yang, J. Pichardo, N. Butkiewicz, A. Prongay, N. Yao, and V. Girijavallabhan Bioorg. Med. Chem. Lett. 14 2004 5751
13. Saksena, A. K., et al., U.S. Patent 6800434 B2, 2004.
14. J.M. Bennett, A.D. Campbell, A.J. Campbell, M.G. Carr, R.M. Dunsdon, J.R. Greening, D.N. Hurst, N.S. Jennings, P.S. Jones, S. Jordan, P.B. Kay, M.A. O'Brien, J. King-Underwood, T.M. Raynham, C.S. Wilkinson, T.C.I. Wilkinson, and F.X. Wilson Bioorg. Med. Chem. Lett. 11 2001 355
15. W. Han, Z. Hu, X. Jiang, and C.P. Decicco Bioorg. Med. Chem. Lett. 10 2000 711
16. M. Llinàs-Brunet, M. Bailey, R. Déziel, G. Fazal, V. Gorys, S. Goulet, T. Halmos, R. Maurice, M. Poirier, M. Poupart, J. Rancourt, D. Thibeault, D. Wernic, and D. Lamarre Bioorg. Med. Chem. Lett. 8 1998 2719
17. S. Bogen, A.K. Saksena, A. Arasappan, H. Gu, F.G. Njoroge, V. Girijavallabhan, J. Pichardo, N. Butkiewicz, A. Prongay, and V. Madison Bioorg. Med. Chem. Lett. 15 2005 4515
18. D.A. Roberts, R.H. Bradbury, D. Brown, A. Faull, D. Griffiths, S.J. Major, A.A. Oldman, R.J. Pearce, A.H. Ratcliffe, J. Revill, and D. Waterson J. Med. Chem. 33 1990 2326
19. M. Passerini, and G. Ragni Gazz. Chim. Ital. 61 1931 964
20. D. Marquarding, G. Gokel, P. Hoffmann, and I. Ugi Isonitrile Chemistry 1971 Academic Press New York Chapter 7
21. J.R. Falck, and S. Manna Tetrahedron Lett. 22 1981 619
22. D.B. Dess, and J.C. Martin J. Org. Chem. 48 1983 4155
23. D.B. Dess, and J.C. Martin J. Am. Chem. Soc. 113 1991 7277
24. Use of large excess of heptane is required during work-up to avoid concentration of TFA and subsequent elimination of the hydroxyl group.
25. J.R. Luly, J.F. Dellaria, J.J. Plattner, J.L. Soderquist, and N. Yi J. Org. Chem. 52 1987 1487
26. 3 led only to the dicyclopropyl adduct below..
27. Enzyme assay: the HCV NS3 serine protease inhibitory value is provided as K i *. For a definition of K i * and discussion, see: J.F. Morrison, and C.T. Walsh A. Meister Adv. Enzymol. Vol. 61 1988 201 301
28. R. Zhang, B.M. Beyer, J. Durkin, R. Ingram, F.G. Njoroge, W.T. Windsor, and B.A. Malcolm Anal. Biochem. 270 1999 268 For the present study, the substrate Ac-DTEDVVP(Nva)-O-PAP was employed
29. Replicon assay: V. Lohmann, F. Korner, J.-O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager Science 285 1999 110
30. K. Blight, A. Kolykhalov, and C. Rice Science 290 2000 1972
31. A.S. Dutta, and M. Giles J. Chem. Soc., Perkin Trans. 1 1976 244
32. J. Gante Synthesis 1989 405
33. Crystallographic data for the structures in this paper have been deposited with the RCSB Protein Data Bank as PDB ID 2F9V. The structural details can be viewed at www.rcsb.org using the ID number above.
34. A.F. Spatola B. Weinstein Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins 1983 Marcel Dekker New York 267 357