Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles

Journal of Medicinal Chemistry

Volumn 49, Issue 3, 2006, Pages 995-1005

  Chen, Kevin X ^a   Njoroge, F George ^a   Arasappan, Ashok ^a   Venkatraman, Srikanth ^a   Vibulbhan, Bancha ^a   Yang, Weiying ^a   Parekh, Tejal N ^a   Pichardo, John ^a   Prongay, Andrew ^a   Cheng, Kuo Chi ^a   Butkiewicz, Nancy ^a   Yao, Nanhua ^a   Madison, Vincent ^a   Girijavallabhan, Viyyoor ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; LEUKOCYTE ELASTASE; MACROCYCLIC COMPOUND; NONSTRUCTURAL PROTEIN 3; PENTAPEPTIDE; PROLINE; SERINE PROTEINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BIOAVAILABILITY; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYCLIZATION; DERIVATIZATION; DRUG POTENCY; HEPATITIS; HEPATITIS C VIRUS; NONHUMAN; RAT; REPLICON; STRUCTURE ANALYSIS; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY;

ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; CYCLIZATION; HEPACIVIRUS; HUMANS; LEUKOCYTE ELASTASE; MACROCYCLIC COMPOUNDS; MODELS, MOLECULAR; OLIGOPEPTIDES; PROLINE; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 32344431531     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050820s     Document Type: Article

References (54)

1. (a) Cohen, J. The Scientific Challenge of Hepatitis C. Science 1999, 285, 26-30.
2. (b) 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.
3. (c) Cuthbert, J. A. Hepatitis C: Progress and Problems. Clin. Microbiol. Rev. 1994, 7, 505-532.
4. (a) Neumann, A. U.; Lam, N. P.; Dahari, H.; Gretch, D. R.; Wiley: T. E.; Layden, T. J.; Perelson, A. S. Hepatitis C Virus Dynamics in vivo and the Antiviral Efficacy of Interferon-α Therapy. Science 1998, 282, 103-107.
5. (b) Rosen, H. R.; Gretch, D. R. Hepatitis C Virus: Current Understanding and Prospects for Future Therapies. Mol. Med. Today 1999, 5, 393-399.
6. (c) Di Bisceglie, A. M.; McHutchison, J.; Rice, C. M. New therapeutic strategies for hepatitis C. Hepatology 2002, 35, 224-231.
7. (a) Lindenbach, B. D.; Rice, C. M. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436, 933-938.
8. (b) Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M. Hepatitis C Virus-Encoded Enzymatic Activities and Conserved RNA Elements in the 3′ Nontranslated Region Are Essential for Virus Replication In Vivo. J. Virol. 2000, 74, 2046-2051.
9. Lesk, A. M.; Fordham, W. D. Conservation and Variability in the Structure of Serine Proteinase of the Chymotrypsin Family. J. Mol. Biol. 1996, 258, 501-537.
10. De Francesco, R.; Steinkuhler, C. Structure and Function of the Hepatitis C Virus NS3-NS4A Protease. Curr. Top. Microbiol. Immunol. 2000, 242, 149-169.
11. (a) Yan, Y.; Li, Y.; Munshi, S.; Sardana, V.; Cole, J. L.; Sardana, M.; Steinkuehler, C.; Tomei, L.; De Francesco, R.; Kuo, L. C.; Chen, Z. Complex of NS3 protease and NS4A Peptide of BK strain Hepatitis C Virus: a 2.2 A resolution structure in a hexagonal crystal form. Protein Sci. 1998, 7, 837-847.
12. (b) Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. Inhibition of Hepatitis C Virus NS3/NS4A Protease: The Crystal Structures of Two Protease-Inhibitor Complexes. J. Biol. Chem. 2000, 275, 7152-7157.
13. (a) De Francesco, R.; Migliaccio, G. Challenges and Successes in Developing New Therapies for Hepatitis C. Nature 2005, 436, 953-960.
14. (b) Tan, S.-L.; He, Y.; Huang, Y.; Gale, M., Jr. Strategies for Hepatitis C Therapeutic Intervention: Now and Next. Curr. Opin. Pharmacol. 2004, 4, 465-470.
15. (c) Malancona, S.; Colarrusso, S.; Ontoria, J. M.; Marchetti, A.; Poma, M.; Stansfield, I.; Laufer, R.; Marco, A. D.; Taliani, M.; Verdirame, M.; Gonzalez-paz, O.; Matassa, V. G.; Narjes, F. SAR and Pharmacokinetics Studies on Phenethylamide Inhibitors of the Hepatitis C Virus. Bioorg. Med. Chem. Lett. 2004, 14, 4575-4579.
16. (d) Llinas-Brunet, M.; Bailey, M. D.; Ghiro, E.; Gorys, V.; Halmos, T.; Poirier, M.; Rancourt, J.; Goudreau, N. A Systematic Approach to the Optimization of Substrate-Based Inhibitors of the Hepatitis C Virus NS3 Protease: Discovery of Potent and Specific Tripeptide Inhibitors J. Med. Chem. 2004, 47, 6584-6594.
17. (e) Andrews, D. M.; Barnes, M. C.; Dowle, M. D.; Hind, S. L.; Johnson, M. R.; Jones, P. S.; Mills, G.; Patikis, A.; Pateman, T. J.; Redfern, T. J.; Ed Robinson, J.; Slater, M. J.; Trivedi, N. Pyrrolidine-5,5-trans-Lactams. 5. Pharmacokinetic Optimization of Inhibitors of Hepatitis C Virus NS3/4A Protease. Org. Lett. 2003, 5, 4631-4634.
18. (f) Zhang, X. Inhibitors of Hepatitis C-A Review of the Current Patent Literature. Idrugs 2002, 5, 154-158.
19. (g) Dymock, B. W. Emerging Therapies for Hepatitis C Virus Infection. Expert Opin. Emerging Drugs 2001, 6, 13-42.
20. (h) Dymock, B. W.; Jones, P. S.; Wilson, F. X. Novel Approaches to the Treatment of Hepatitis C Virus. Antiviral Chem. Chemother. 2000, 11, 79-96.
21. (i) Zhang, R.; Durkin, J. P.; Windsor, W. T. Azapeptides as Inhibitors of the Hepatitis C Virus NS3 Serine Protease. Bioorg. Med. Chem. Lett. 2002, 12, 1005-1008.
22. (j) Ingallinella, P.; Fattori, D.; Altamura, S.; Steinkuhler, C.; Koch, U.; Cicero, D.; Bazzo, R.; Cortese, R.; Bianchi, E.; Pessi, A. Prime Site Binding Inhibitors of a Serine Protease: NS3/4A of Hepatitis C Virus. Biochemistry. 2002, 41, 5483-5492.
23. (k) Beevers, R.; Carr, M. G.; Jones, P. S.; Jordan, S.; Kay, P. B.; Lazell, R. C.; Raynham, T. M. Solution and Solid-Phase Synthesis of Potent Inhibitors of Hepatitis C Virus NS3 Protease. Bioorg. Med. Chem. Lett. 2002, 12, 641-643.
24. For BILN-2061, see: (a) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bös, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H. Kukolj, G.; Lagacé, L.; LaPlante, S. R. Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens, R. E.; George, T. S.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; and Llinàs-Brunet M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus Nature 2003, 426, 186-189.
25. (b) Tsantrizos, Y. S.; Bolger, G.; Bonneau, P.; Cameron, D. R.; Gordreau, N.; Kukolj, G.; LaPlante, S. R.; Llinas-Brunet, M.; Nar, H.; Lamarre, D. Macrocyclic Inhibitors of the NS3 Protease as Potential Therapeutic Agents of Hepatitis C Virus Infection. Angew. Chem., Int. Ed. 2003, 42, 1355-1360.
26. For VX-950, see: (c) Yip, Y.; Victor, F.; Lamar, J.; Johnson, R.; Wang, Q.; May; G.; John I.; Yumibe, N.; Wakulchik, M.; Munroe, J.; Chen, S.-H. P4 and P1′ optimization of bicycloproline P2 bearing tetrapeptidyl α-ketoamides as HCV protease inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5007-5011.
27. (d) Perni, R. The Discovery of VX-950, an Inhibitor of the HCV NS3-4A Protease in Clinical Development. Gordon Research Conference, New London, NH, Aug 7-12, 2005.
28. West, M. L.; Fairlie, D. P. Targeting HIV-1 protease: A Test of Drug-Design Methodologies. Trends Pharm. Sci. 1995, 16, 67-75.
29. Fairlie, D. P.; West, M. L.; Wong, A. K. Towards Protein Surface Mimetics. Curr. Med. Chem. 1998, 5, 29-62.
30. Boger, D. L.; Kim, S. H.; Miyazaki, S.; Strittmatter, H.; Weng, J.-H.; Mori, Y.; Rogel, O.; Castle, S. L.; McAtee, J. J. Total Synthesis of the Teicoplanin Aglycon. J. Am. Chem. Soc. 2000, 122, 7416-7417.
31. (b) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Total Syntheses of Vancomycin and Eremomycin Aglycons. Angew. Chem., Int. Ed. 1998, 37, 2700-2704.
32. (c) Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.; Trotter, B. W.; Katz, J. L. Nonconventional Stereochemical Issues in the Design of the Synthesis of the Vancomycin Antibiotics: Challenges Imposed by Axial and Nonplanar Chiral Elements in the Heptapeptide Aglycons Angew. Chem., Int. Ed. 1998, 37, 2704-2708.
33. (e) Rama Rao, A.; Garjar, M.; Reddy, K.; Rao, A. Studies directed toward the synthesis of vancomycin and related cyclic peptides. Chem. Rev. 1995, 95, 2135-2167.
34. (f) Mtsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff, H. B.; Tanaka, H.; Omura, S. Chloropeptins I and II, Novel Inhibitors Against gp120-CD4 Binding from Streptomyces sp. J. Antibiot. 1994, 47, 1173-1174.
35. (g) Matsuzaki, K.; Ogino, T.; Sunazuka, T.; Tanaka, H.; Omura, S. Chloropeptins, New Anti-HIV Antibiotics Inhibiting gp120-CD4 Binding from Streptomyces sp. II. Structure Elucidation of Chloropeptin I. J. Antibiot. 1997, 50, 66-69.
36. McGeary, R. P.; Fairlie, D. P. Macrocyclic Peptidomimetics: Potential for Drug Development. Curr. Opin. Drug Discovery Dev. 1998, 1, 208-217.
37. (a) Llinas-Brunet, M.; Bailey, M. D.; Fazal, G.; Goulet, S.; Halmos, T.; LePlante, S.; Maurice, R.; Poirier, M.; Poupart, M.-A.; Thibeault, D.; Wernic, D.; Lamarre, D. Peptide-Based Inhibitors of the Hepatitis C Virus Serine Protease. Bioorg. Med. Chem. Lett. 1998, 8, 1713-1718.
38. (b) Steinkuhler, C.; Biasiol, G.; Brunetti, M.; Urbani, A.; Koch, U.; Cortese, R.; Pessi, A.; De Francesco, R. Product Inhibition of the Hepatitis C Virus NS3 Protease. Biochemistry 1998, 37, 8899-8905.
39. (a) Lin, C.; Lin, K.; Luong, Y.-P.; Rao, B. G.; Wei, Y.; Brennan, D. L.; Fulghum, J. R.; Hsiao, H.-M.; Ma, S.; Maxwell, J. P.; Cottrell, K. M.; Perni, R. B.; Gates, C. A.; Kwong, A. D. In Vitro Resistance Studies of Hepatitis C Virus Serine Protease Inhibitors, VX-950 and BILN 2061. J. Biol. Chem. 2004, 279, 17508-17514.
40. (b) Sun, D. X.; Liu, L.; Heinz, B.; Kolykhalov, A.; Lamar, J.; Johnson, R. B.; Wang, Q. M.; Yip, Y.; Chen, S.-H. P4 Cap Modified Tetrapeptidyl α-Ketoamides as Potent HCV NS3 Protease Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 4333-4338.
41. (c) Yip, Y.; Victor, F.; Lamar, J.; Johnson, R.; Wang, Q. M.; Glass, J. I.; Yumibe, N.; Wakulchik, M.; Munroe, J.; Chen, S.-H. P4 and P1′ Optimization of Bicycloproline P2 Bearing Tetrapeptidyl α-Ketoamides as HCV Protease Inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5007-5011.
42. (d) Perni, R. B.; Farmer, L. J.; Cottrell, K. M.; Court, J. J.; Courtney, L. F.; Deininger, D. D.; Gates, C. A.; Harbeson, S. L.; Kim, J. L.; Lin, C.; Lin, K.; Luong, Y.-P.; Maxwell, J. P.; Murcko, M. A.; Pitlik, J.; Rao, B. G.; Schairer, W. C.; Tung, R. D.; Van Drie, J. H.; Wilson, K.; Thomson, J. A. Inhibitors of Hepatitis C Virus NS3/4A Protease. Part 3: P2 Praline Variants. Bioorg. Med. Chem. Lett. 2004, 14, 1939-1942.
43. Schering-Plough Research Institute. Unpublished results.
44. (a) Chen, K. X.; Arasappan, A.; Njoroge, F. G.; Vibulbhan, B.; Buevich, A.; Chan, T.-M.; Girijavallabhan, V. Syntheses of Novel 4-tert-Alkyl Ether Proline-Based 16- and 17-Membered Macrocyclic Compounds. J. Org. Chem. 2002, 67, 2730-2733.
45. (b) Arasappan, A.; Chen, K. X.; Njoroge, F. G.; Parekh, T. N.; Girijavallabhan, V. Novel Dipeptide Macrocycles from 4-Oxo, -Thio, and -Amino-Substituted Proline Derivatives. J. Org. Chem. 2002, 67, 3923-3926.
46. Dess, D. B.; Martin, J. C. A Useful 12-1-5 Triacetoxyperiodinane (the Dess-Martin Periodinane) for the Selective Oxidation of Primary or Secondary Alcohols and a Variety of Related 12-1-5 Species. J. Am. Chem. Soc. 1991, 113, 7277-7287.
47. Zhang, R.; Beyer, B. M.; Durkin, J.; Ingram, R.; Njoroge, F. G.; Windsor, W. T.; Malcolm, B. A. A Continuous Spectrophotometric Assay for the Hepatitis C Virus Serine Protease. Anal. Biochem. 1999, 270, 268-275. The substrate Ac-DTEDVVP(Nva)-O-PAP was used in the present study.
48. Taremi, S. S.; Beyer, B.; Maher, M.; Yao, N.; Prosise, W.; Weber, P. C.; Malcolm, B. A. Construction, Expression, and Characterization of a Novel Fully Activated Recombinant Single-Chain Hepatitis C Virus Protease. Protein Sci. 1998, 7, 2143-1249.
49. i* and discussions, see: Morrison, J. F.; Walsh, C. T. In Advances in Enzymology; Meister, A., Ed.; 1988; Vol. 61, pp 201-301.
50. (a) Tidwell, T. T. Oxidation of Alcohols to Carbonyl Compounds via Alkoxysulfonium Ylides: The Moffatt, Swern and Related Oxidations. Org. React. 1990, 39, 297.
51. (b) Epstein, W. W.; Sweat, F. W. Dimethyl Sulfoxide Oxidations. Chem. Rev. 1967, 67, 247-260.
52. (a) Chung, V.; Carroll, A. R.; Gray, N. M.; Parry, N. R.; Thommes, P. A.; Viner, K. C.; D'Souza, E. A. Development of Cell-Based Assays for In Vitro Characterization of Hepatitis C Virus NS3/4A Protease Inhibitors. Antimicrob. Agents Chemother. 2005, 49, 1381-1390.
53. (b) Blight, K. J.; Kolykhalov, A. A.; Rice, C. M. Science 2000, 290, 1972-1974.
54. (c) 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.