The discovery and development of boceprevir

Expert Opinion on Drug Discovery

Volumn 8, Issue 11, 2013, Pages 1439-1447

  Rotella, David P ^a  

^a MONTCLAIR STATE UNIVERSITY   (United States)

Author keywords

Antiviral agent; Boceprevir; NS3 protease; Peptidomimetic; Protease inhibitor

Indexed keywords

ANTIVIRUS AGENT; BOCEPREVIR; NSE PROTEASE; NSE PROTEASE INHIBITOR; PEGINTERFERON; PEPTIDOMIMETIC AGENT; PLACEBO; RIBAVIRIN; UNCLASSIFIED DRUG; VIRUS ENZYME; VIRUS RNA;

ANEMIA; DRUG EFFICACY; DRUG POTENCY; DRUG RESPONSE; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DYSGEUSIA; ENZYME INHIBITION; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IN VITRO STUDY; MOLECULAR BIOLOGY; NEUTROPENIA; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN STRUCTURE; REVIEW; STRUCTURE ACTIVITY RELATION; TREATMENT OUTCOME;

ANTIVIRAL AGENTS; DRUG DISCOVERY; HEPATITIS C; HUMANS; MOLECULAR TARGETED THERAPY; PROLINE; PROTEASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84886602795     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.843525     Document Type: Review

References (29)

1. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a DNA clone from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244: 359-62. This article describes identification of the virus.
2. Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244: 362-4. This article describes an assay to characterize the virus.
3. WHO fact sheet. 2012.Available from: http://www.who. int/mediacentre/ factsheets/fs164/en/
4. Qiu P, Cai X-Y, Ding W, et al. HCV genotyping using statistical classification approach. J Biomed Sci 2009;16: 62-71
5. Manns MP, McHutchinson JG, Gordon SC. Peg interferon alfa02b plus ribavirin compared with interferon alfa-2b for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358: 958-65
6. Poynard T, McHutchison JG, Goodman ZD. Is an "a la carte" combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C. Hepatology 2000;31: 211-8
7. Sampath A, Padmanabhan R. Molecular targets for flavivirus drug discovery. Antiviral Res 2009;81: 6-15
8. Tomei L, Failla C, Santolini E. NS3 is a serine protease required for processing of hepatitis C virus polyprotein. J Virol 1993;67: 4017-26. Characterization of the molecular target of boceprevir.
9. Bartenschlager R, Ahlborn-Laake L,Mous J. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type protease required for cleavage at the NS3/4 and NS4/5 junctions. J Virol 1993;67: 3835-44. Characterization of the molecular target of boceprevir.
10. McCoy MA, Senior MM, Gesell JJ, et al. Solution structure and dynamics of the single-chain hepatitis C virus NS3 protease NS4A cofactor complex. J Mol Biol 2001;305: 1099-110
11. Lemke CT, Goudreau N, Zhao S, et al. Combined X-ray, NMR and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335. J Biol Chem 2011;286: 11434-43
12. Saalau-Bethell SM, Woodhead AJ, Chessari G, et al. Discovery of an allosteric mechanism for the regulation of HCV NS3 protease function. Nat Chem Biol 2012;8: 920-5
13. Zhang R, Beyer BM, Durkin J, et al. A continuous spectrophotometric assay for the hepatitis C virus serine protease. Anal Biochem 1999;270: 268-75
14. Venkatraman S, Bogen SL, Arasappan A, et al. Discovery of (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), 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: 6074-86 .. Article describes the final stages of boceprevir optimization.
15. Arasappan A, Njoroge FG, Chan T-Y, et al. Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency. Bioorg Med Chem Lett 2005;15: 4180-4
16. Bogen SL, Ruan S, Liu R, et al. Depeptidization efforts on the P3-P2' aketoamide inhibitors of HCV NS3-4A serine protease: effect on HCV replicon activity. Bioorg Med Chem Lett 2006;16: 1621-7
17. Bogen SL, Arasappan A, Bennett F, 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: 2750-7
18. Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in human infected with hepatitis C virus. Nature 2003;426: 186-9
19. McGeary RP, Fairlie DP. Macrocylic peptidomimetics: potential for drug development. Curr Opin Drug Discov Dev 2003;1: 208-17
20. Chen KX, Njoroge FG, Arasappan A, et al. Novel potent hepatitis C virus NS3 protease inhibitors derived from proline-based macrocycles. J Med Chem 2006;49: 995-1005
21. Chen KX, Njoroge FG, Vibulbhan B, et al. Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew Chem Int Ed Eng 2005;44: 7024-8
22. Venkatraman S, Velazquez F,WuW, et al. Discovery and structure-activity relationship of P1-P3 ketoamide derived macrocyclic inhibitors of hepatitis C NS3 protease. J Med Chem 2009;52: 336-46
23. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peg interferon alfa 2b and ribavirin in treatment naïve patients with genotype1 hepatitis C infection (SPRINT-1): an open-label, randomized, multicentre phase 2 trial. Lancet 2010;376: 705-16 .. Clinical demonstration of efficacy.
24. Ogert RA, Howe JA, Vierling JM, et al. Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-a2b and ribavirin in patients with chronic hepatitis in the SPRINT-1 trial. Antivir Ther 2013;18: 387-97
25. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. New Eng J Med 2011;364: 1195-206 .. Clinical demonstration of efficacy.
26. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic hepatitis C genotype 1 infection. New Eng J Med 2011;364: 1207-17
27. Silva MO, Treitel M, Graham DJ, et al. Antiviral activity of boceprevir monotherapy in treatment-naïve subjects with chronic hepatitis C genotype 2/3. J Hepatol 2013;59: 31-7
28. Boceprevir label information
29. Kieran J, Schmitz S, O'Leary A, et al. The relative efficacy of boceprevir and telaprevir in the treatment of hepatitis C virus genotype 1. Clin Infect Dis 2013;56: 228-35