Second-generation highly potent and selective inhibitors of the hepatitis C virus NS3 serine protease

Journal of Medicinal Chemistry

Volumn 52, Issue 5, 2009, Pages 1370-1379

  Chen, Kevin X ^a   Nair, Latha ^a   Vibulbhan, Bancha ^a   Yang, Weiying ^a   Arasappan, Ashok ^a   Bogen, Stephane L ^a   Venkatraman, Srikanth ^a   Bennett, Frank ^a   Pan, Weidong ^a   Blackman, Melissa L ^a   Padilla, Angela I ^a   Prongay, Andrew ^a   Cheng, Kuo Chi ^a   Tong, Xiao ^a   Shih, Neng Yang ^a   Njoroge, F George ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [[[[[(2,2 DIMETHYL[(4 METHYL 2,6 DIOXO 1 PIPERIDINYL)METHYL]PROPYL]AMINO]CARBONYL]AMINO] 3,3 DIMETHYL 1 OXOBUTYL] N [1 [1,2 DIOXO 2 (2 PROPENYLAMINO)ETHYL]PENTYL] 6,6 DIMETHYL 3 AZABICYCLO[3.1.0]HEXANE CARBOXAMIDE; 3 [[[[[[(4,4 DIMETHYL 2,6 DIOXO 1 PIPERIDINYL) METHYL] 2,2 DIMETHYLPROPYL]AMINO]CARBONYL]AMINO] 3,3 DIMETHYL 1 OXOBUTYL] N [1 [1,2 DIOXO 2 (2 PROPENYLAMINO)ETHYL]PENTYL] 6,6 DIMETHYL 3 AZABICYCLO[3.1.0]HEXANE CARBOXAMIDE; 3 [CYCLOHEXYL 2 [[[[[(4,4 DIMETHYL 2,6 DIOXO 1 PIPERIDINYL) METHYL] 2,2 DIMETHYLPROPYL]AMINO]CARBONYL]AMINO]ACETYL] N [1 [1,2 DIOXO 2 (2 PROPENYLAMINO)ETHYL]PENTYL] 6,6 DIMETHYL 3 AZABICYCLO[3.1.0]HEXANE CARBOXAMIDE; HYDROGEN; IMIDE; N[1 (CYCLOPROPYLETHYL) 2,3 DIOXO 3 (2 PROPENYLAMINO)PROPYL] 3 [[[[[[(4,4 DIMETHYL 2,6 DIOXO 1 PIPERIDINYL) METHYL] 2,2 DIMETHYLPROPYL]AMINO] CARBONYL]AMINO] 3,3 DIMETHYL 1 OXOBUTYL] 6,6 DIMETHYL 3 AZABICYCLO[3.1.0]HEXANE CARBOXAMIDE; N[1 (CYCLOPROPYLMETHYL) 2,3 DIOXO 3 (2 PROPENYLAMINO)PROPYL] 3 [[[[[[(4,4 DIMETHYL 2,6 DIOXO 1 PIPERIDINYL) METHYL] 2,2 DIMETHYLPROPYL]AMINO] CARBONYL]AMINO] 3,3 DIMETHYL 1 OXOBUTYL] 6,6 DIMETHYL 3 AZABICYCLO[3.1.0]HEXANE CARBOXAMIDE; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG STRUCTURE; HEPATITIS C VIRUS; HYDROGEN BOND; NONHUMAN; RAT;

ANIMALS; ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; DOGS; HAPLORHINI; HEPACIVIRUS; HYDROGEN BONDING; IMIDES; LEUCINE; MODELS, MOLECULAR; PIPERIDONES; RATS; SERINE PROTEINASE INHIBITORS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; UREA; VIRAL NONSTRUCTURAL PROTEINS;

EID: 64349097307     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm801238q     Document Type: Article

References (40)

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. Monto, A.; Wright, T. L. The Epidemiology and Prevention of Hepatocellular Carcinoma. Semin. Oncol. 2001, 441.
5. (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-a Therapy. Science 1998, 282, 103-107.
6. (b). Rosen, H. R.; Gretch, D. R. Hepatitis C Virus: Current Understanding and Prospects for Future Therapies. Mol. Med. Today 1999, 5, 393-399.
7. (c). Di Bisceglie, A. M.; McHutchison, J.; Rice, C. M. New therapeutic strategies for hepatitis C. Hepatology 2002, 35, 224-231.
8. (a). Lindenbach, B. D.; Rice, C. M. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436, 933-938.
9. (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.
10. 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.
11. De Francesco, R.; Steinkuhler, C. Structure and Function of the Hepatitis C Virus NS3-NS4A Protease. Curr. Top. iMicrobiol Immunol. 2000, 242, 149-169.
12. (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.
13. (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.
14. (a). De Francesco, R.; Migliaccio, G. Challenges and Successes in Developing New Therapies for Hepatitis C. Nature 2005, 436, 953-960.
15. (b) Tan, S.-L.; He, Y.; Huang, Y.; Gale, M., Jr. Strategies for Hepatitis C Therapeutic Intervention: Now and Next. Curr. Ovin. Pharmacol 2004, 4, 465-470.
16. (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 Phenethyla- mide Inhibitors of the Hepatitis C Virus. Bioorg. Med. Chem. Lett. 2004, 14, 4575-4579.
17. (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.
18. (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.
19. (f). Zhang, X. Inhibitors of Hepatitis C-A Review of the Current Patent Literature. Idrugs 2002, 5, 154-158.
20. (g). Dymock, B. W. Emerging Therapies for Hepatitis C Virus Infection. Exvert Ovin. Emerging Drugs 2001, 6, 13-42.
21. (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.
22. (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.
23. (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.
24. (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.
25. 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.; Lagace, 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.; Llinàs-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003, 426, 186-189.
26. (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.
27. For VX-950, see: (a). 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 tetrapep- tidyl α-ketoamides as HCV protease inhibitors. Bio. Med. Chem. Lett. 2004, 14, 5007-5011.
28. (b). Perni, R. The Discovery of VX-950, an Inhibitor of the HCV NS3-4A Protease in Clinical Development. Gordon Research Conference, New London, NH, August 7-12, 2005, 2005.
29. For SCH 503034, see: (a). 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.
30. (b). 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 (1R,5 S)-N-[3-Amino-1-(cyclobutylmethyl)-2-3-dioxo- propyl]-3-[2(S)-[[[(1,1- dimethylethyl)-amino]carbonyl]amino]-3,3-di- methyl-1-oxobutyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-2(S)-car- boxamide (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.
31. Chen, K. X.; Njoroge, F. G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T.; Pichardo, J.; Prongay, A.; Cheng, K.-C.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based Macrocycles. J. Med. Chem. 2006, 49, 995-1005.
32. Dess, D. B.; Martin, J. C. A Useful 12-I-5 Triacetoxyperiodinane (the Dess-Martin Periodinane) for the Selective Oxidation of Primary or Secondary Alcohols and a Variety of Related 12-I-5 Species. J. Am. Chem. Soc. 1991, 113, 7277-7287.
33. (a). Hughes, D. L. The Mitsunobu Reaction. Org. React. 1992, 42, 335.
34. (b). Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1-28.
35. 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.
36. 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.
37. i* and discussions, see: (a). Morrison, J. F.; Walsh, C. T. Adv. Enzymol. 1988, 61, 201-301.
38. (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.
39. (b). Blight, K. J.; Kolykhalov, A. A.; Rice, C. M. Science 2000, 290, 1972-1974.
40. (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. JM801238Q