Intervention of Hepatitis C Replication through NS3-4A, the Protease Inhibitor Boceprevir

Antiviral Drugs: From Basic Discovery through Clinical Trials

Volumn , Issue , 2011, Pages 239-255

  Venkatraman, Srikanth ^a   Njoroge, F George ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Boceprevir, and phase III clinical trials drug authority review, and HCV treatment; Intervention of hepatitis C replication, through NS3 4A protease inhibitor boceprevir; Synergistic effects, influencing enzyme binding and HNE HCV selectivity

Indexed keywords

EID: 84886052413     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470929353.ch17     Document Type: Chapter

References (52)

1. World Health Organization. Fact sheet 164, Oct. 2000.
2. Wasley, A., et al. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin. Liver Dis. 2000, 20, 1-16.
3. Brown, R. S., Jr., et al. Scope of worldwide hepatitis C problem. Liver Transpl. 2003, 9 (11), S10-S13.
4. McHutchison, J. G., et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Engl. J. Med. 1998, 339, 1485-1492.
5. Davis, G. L., et al. Interferon alfa-2b alone or in combination with ribavirin for treatment of relapse of chronic hepatitis C. N. Engl. J. Med. 1998, 339, 1493-1499.
6. Zeuzem, S., et al. Peginterferon alfa-2a in patientswith chronic hepatitis C. N. Engl. J. Med. 2000, 343, 1666-1172.
7. Heathcote, E. J., et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N. Engl. J. Med. 2000, 343, 1673-1680.
8. Manns, M. P., et al. Peginterferon alfa-2b plus ribavirin comparedwith interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001, 358, 958-965.
9. Lamarre, D., et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003, 426, 186-189.
10. Labrador, L., et al. Hepatitis C virus NS3/4A protease inhibitors. Recent Pat. Anti-infect. Drug Discov. 2008, 3, 157-167.
11. Thompson, A., et al. Directly acting antivirals for the treatment of patients with hepatitis C infection: a clinical development update addressing key future challenges. J. Hepatol. 2009, 50, 184-194.
12. De Francesco, R., et al. Challenges and successes in developing new therapies for hepatitis C. Nature 2005, 436, 953-960.
13. Tsantrizos, Y. S. Peptidomimetic therapeutic agents targeting the protease enzyme of the human immunodeficiency virus and hepatitis C virus. Acc. Chem. Res. 2008, 41, 1252-1263.
14. Sheldon, J., et al. Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection. Expert Opin. Invest. Drugs 2007, 16, 1171-1181.
15. Chen, K. X., et al. A review of HCV protease inhibitors. Curr. Opin. Invest. Drugs 2009, 10, 821-837.
16. Brazil, M. Antiviral drugs: macrocyclic inhibitor for hepatitis C. Nat. Rev. Drug Discov. 2003, 212, 945.
17. Tsantrizos, Y. S., et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew. Chem. Int. Ed. 2003, 42, 1356.
18. Kaito, M., et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J. Gen. Virol. 1994, 75, 1755-1760.
19. Bartenschlager, R. The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy. J. Viral. Hepatitis 1999, 6, 165-181.
20. Bartenschlager, R., et al. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. J. Virol. 1993, 67, 3835-3844.
21. Reed, K. E., et al. Molecular characterization of hepatitis C virus. In Hepatitis C Virus, Reesink H. W., Ed., S. Karger, Basel, Switzerland, 1998, pp. 1-37.
22. Lindenbach, B. D., et al. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436, 933-938.
23. Perni, R. B., et al. Inhibitors of hepatitis C virus NS3·4A protease: 3. P2 proline variants. Bioorg. Med. Chem. Lett. 2004, 14, 1939-1942.
24. McCauley, J.A., et al. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C verus NS3/4A protease inhibitor. J. Med. Chem. 2010, 53, 2443-2463.
25. Seiwert, S. D., et al. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Animicrob. Agents Chemother. 2008, 52, 4432-4441.
26. Raboisson, P., et al. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg. Med. Chem. Lett. 2008, 18, 4853-4858.
27. Yan, Y., et al. Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 Å resolution structure in a hexagonal crystal form. Prot. Sci. 1998, 7, 837-847.
28. Love, R. A., et al. The crystal structure of hepatitis C virus NS3 proteinase reveals a trypsin-like fold and a structural zinc binding site. Cell 1996, 87, 331-342.
29. Kim, J. L., et al. Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure 1998, 6, 89-100.
30. Kwong, A. D., et al. Hepatitis C virus NS3/4A protease. Antiviral Res. 1998, 40, 1-18.
31. J. L. Kim, et al. Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide. Cell 1996, 87, 343.
32. Steinkuhler, C., et al. Activity of purified hepatitis C virus protease NS3 on peptide substrates. J. Virol. 1996, 70, 6694-6700.
33. Urbani, A., et al. A substrate specificity of the hepatitis C virus serine protease NS3. J. Biol. Chem. 1997, 272, 9204-9209.
34. Kolykhalov, A. A., et al. Specificity of the hepatitis C virus NS3 serine protease: effects of substitutions at the 3/4A, 4A/4B, 4B/5A, and 5A/5B cleavage sites on polyprotein processing. J. Virol. 1994, 68, 7525-7533.
35. Zhang, R., et al. A continuous spectrophotometric assay for the hepatitis C virus serine protease. Anal. Biochem. 1999, 270, 268-275.
36. Bogen, S. L., et al. Depeptidization efforts on P3-P'2 α-ketoamide inhibitors of HCV NS3-4A serine protease: effect on HCV replicon activity. Bioorg. Med. Chem. Letts. 2006, 16, 1621-1627.
37. Lohmann, V., et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 1999, 285, 110-113.
38. 1 cyclopropyl alanine combination for improved potency. Bioorg. Med. Chem. Lett. 2005, 15, 4515-4519.
39. Tyndall, J. D. A., et al. Macrocycles mimic the extended peptide conformation recognized by aspartic, serine, cysteine, and metallo proteases. Curr. Med. Chem. 2001, 8, 893-907.
40. Venkatraman, S., et al. Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design. J. Med. Chem. 2005, 48, 5088-5091.
41. Chen, K. X., et al. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycle. J. Med. Chem. 2006, 49, 995-1005.
42. Bogen, S. L., et al. Discovery of SCH446211 (SCH6): A new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication. J. Med. Chem. 2006, 49, 2750-2757.
43. Mamai, A., et al. Poly-l-proline type-II peptide mimics based on the 3-azabicyclo[3.1.0]hexane system. J. Org. Chem. 2001, 66, 455-460.
44. Zhang, R., et al. Design, synthesis and evaluation of poly-l-proline type-II peptide mimics based on the 3-azabicyclo[3.1.0]hexane system. J. Org. Chem. 1999, 64, 330-331.
45. Arasappan, A., et al. Novel dipeptide macrocycles from 4-oxo, -thio, and -amino-substituted proline derivatives. J. Org. Chem. 2002, 67, 3923-3926.
46. Cox, K. A., et al. A novel in vivo procedure for the rapid rat pharmacokinetic screening of discovery compounds in rat. Drug Discov. Today 1999, 4, 232-237.
47. Venkatraman, S., et al. Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2-3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)-amino]carbonyl]amio]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034), a selective, potent, orally bioavailable, hepatits C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection. J. Med. Chem. 2006, 49, 6074-6086.
48. Malcolm, B., et al. Sch 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob. Agents Chemother. 2006, 50 (3), 1013-1020.
49. Cheng, K.-C., et al. Use of pre-clinical in vitro and in vivo pharmacokinetics for selection of potent hepatitis C protease inhibitor, boceprevir, for clinical development. Lett. Drug Des. Discover. 2009, 6, 312-318.
50. Prongay, A., et al. Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034): key steps in structure-based optimization. J. Med. Chem. 2007, 50, 2310-2318.
51. Tong, X., et al. Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor Sch 503034. Antiviral Res. 2006, 70, 28-38.
52. Tong, X., et al. Impact of naturally occurring variants of HCV protease on the binding of different classes of protease inhibitors. Biochemistry 2006, 45, 1353-1361.