Challenges in modern drug discovery: A case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection

Accounts of Chemical Research

Volumn 41, Issue 1, 2008, Pages 50-59

  Njoroge, F George ^a   Chen, Kevin X ^a   Shih, Neng Yang ^a   Piwinski, John J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DRUG DERIVATIVE; N (3 AMINO 1 (CYCLOBUTYLMETHYL) 2,3 DIOXOPROPYL) 3 (2 ((((1,1 DIMETHYLETHYL)AMINO)CARBONYL)AMINO) 3,3 DIMETHYL 1 OXOBUTYL) 6,6 DIMETHYL 3 AZABICYCLO(3.1.0)HEXAN 2 CARBOXAMIDE; N-(3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL)-3-(2-((((1,1-DIMETHYLETHYL)AMINO)CARBONYL)AMINO)-3,3-DIMETHYL-1-OXOBUTYL)-6,6-DIMETHYL-3-AZABICYCLO(3.1.0)HEXAN-2-CARBOXAMIDE; NS3 PROTEIN, HEPATITIS C VIRUS; PROLINE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; VIRUS PROTEIN;

ANIMAL; ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG DESIGN; ENZYMOLOGY; HEPATITIS C; HUMAN; MICROBIOLOGICAL EXAMINATION; PHASE 1 CLINICAL TRIAL; STRUCTURE ACTIVITY RELATION; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ANIMALS; CLINICAL TRIALS, PHASE I AS TOPIC; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HEPATITIS C; HUMANS; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; PROLINE; PROTEASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 38949191974     PISSN: 00014842     EISSN: None     Source Type: Journal    
DOI: 10.1021/ar700109k     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, 0. 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) Hoofnagle, J. H. Course and Outcome of Hepatitis C. Hepatology 2002, 36, S21-S29.
5. (b) Alter, H. J.; Seeff, L. B. Recovery, Persistence, and Sequelae in Hepatitis C Virus Infection: A Perspective on Long-Term Outcome. Semin. Liver Dis. 2000, 20, 17-35.
6. (c) Brown, R. S., Jr.; Gaglio, P. J. Scope of Worldwide Hepatitis C Problem. Liver Transplant. 2003, 9, S10-S13.
7. (a) Feld, J. J.; Hoofnagle, J. H. Mechanism of Action of Interferon and Ribavirin in Treatment of Hepatitis C. Nature 2005, 436, 967-972.
8. (b) 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.
9. (c) Fried, M. W.; Shiffman, M. L.; Reddy, D. K. R.; Smith, C.; Marinos, G.; Gonçales, F. L.; Häussinger, D.; Diago, M.; Carosi, G.; Dhumeaux, D.; Craxi, A.; Lin, A.; Hoffman, J.; Yu, J. PEGinterferon α-2a plus Ribavirin for Chronic Hepatitis C Virus Infection. New Engl. J. Med. 2002, 347, 975-982.
10. Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA Clone Derived from a Blood-Borne Non-A, Non-B Viral Hepatitis Genome. Science 1989, 244, 359-362.
11. (a) Lindenbach, B. D.; Rice, C. M. Unravelling Hepatitis C Virus Replication from Genome to Function. Nature 2005, 436, 933-938.
12. (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.
13. (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 Å Resolution Structure in a Hexagonal Crystal Form. Protein Sci. 1998, 7, 837-847.
14. (b) Love, R. A.; Parge, H. E.; Wichersham, J. A.; Hostomsky, Z.; Habuka, N.; Moomaw, E. W.; Adachi, T.; Hostomska, Z. 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.
15. (a) Behrens, S. E.; Tomei, L.; De Francesco, R. Identification and Properties of the RNA-Dependent RNA Polymerase of Hepatitis C Virus. EMBO J. 1996, 15, 12-22.
16. (b) Lesburg, C. A.; Cable, M. B.; Ferrari, E.; Hong, Z.; Mannarino, A. F.; Weber, P. C. Crystal Structure of the RNA-Dependent RNA Polymerase from Hepatitis C Virus Reveals a Fully Encircled Active Site. Nat. Struct. Biol. 1999, 6, 937-943.
17. (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.; Llinàs-Brunet, M. An NS3 Protease Inhibitor with Antiviral Effects in Humans Infected with Hepatitis C Virus. Nature 2003, 426, 186-189.
18. (b) Perni, R. B.; Almquist, S. J.; Byrn, R. A.; Chandorkar, G.; Chaturvedi, P. R.; Courtney, L. F.; Decker, C. J.; Dinehart, K.; Gates, C. A.; Harbeson, S. L.; Heiser, A.; Kalkeri, G.; Kolaczkowski, E.; Lin, K.; Luong, Y.-P.; Rao, B. G.; Taylor, W. P.; Thomson, J. A.; Tung, R. D.; Wei, Y.; Kwong, A. D.; Lin, C. Preclinical Profile of VX-950, a Potent, Selective, And Orally, Bioavailable Inhibitor of Hepatitis C Virus NS3-NS4A Serine Protease. Antimicrob. Agents Chemother. 2006, 50, 899-909.
19. (c) Saha, A. K.; Young, C.; Del Vecchio, A. M.; Bailey, T. A.; Reinhardt, J. A.; Kulkarni, B. A.; Faitg, T. H.; Feng, H.; Rippin, S. R.; Blackledge, C. W.; Rys, D. J.; Lessen, T. A.; Swestock, J.; Deng, Y.; Nitz, T. J.; Chunduru, S.; Chopra, R.; Collett, M.; Pevear, D.; Howe, A. Y. M.; O'Connell, J.; Mansour, T.; Burns, C. J. Discovery of Hcv - 796: A Potent and Orally Bioavailable Hepatitis-C Polymerase Inhibitor under Clinical Development. Abstracts of Papers, 233rd ACS National Meeting, Chicago, IL, USA, March 25-29, 2007.
20. Houghton, M.; Abrignani, S. Prospects for a Vaccine against the Hepatitis C Virus. Nature 2005, 436, 961-966.
21. Lohmann, V.; Korner, 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.
22. Mercer, D. F.; Schiller, D. E.; Elliott, J. F.; Douglas, D. N.; Hao, C.; Rinfret, A.; Addison, W. R.; Fischer, K. P.; Churchill, T. A.; Lakey, J. R. T.; Tyrrell, D. L. J.; Kneteman, N. M. Hepatitis C Virus Replication in Mice with Chimeric Human Livers. Nat. Med. 2001, 7, 927-933.
23. Walker, C. M. Comparative Features of Hepatitis C Virus Infection in Humans and Chimpanzees. Springer Semin. Immunopathol. 1997, 19, 85-98.
24. For a review, see: De Francesco, R.; Migliaccio, G. Challenges and Successes in Developing New Therapies for Hepatitis C. Nature 2005, 436, 953-960.
25. (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.
26. (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.
27. (a) Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, J.; 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.; Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agrawal, S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.; Prongay, A.; Madison, V.; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, Y.; Brisson, J.-M.; Prelusky, D.; Korfmacher, W.; White, R.; Bogdanowich-Knipp, S.; Pavlovsky, A.; Bradley, P.; Saksena, A.; K.; Ganguly, A.; Piwinski, J.; Girijavallabhan, V.; Njoroge, F. G. 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, 6074-6086.
28. (b) Malcolm, B. A.; Liu, R.; Lahser, F.; Agrawal, S.; Belanger, B.; Butkiewicz, N.; Chase, R.; Gheyas, F.; Hart, A.; Hesk, D.; Ingravallo, P.; Jiang, C.; Kong, R.; Lu, J.; Pichardo, J.; Prongay, A.; Skelton, A.; Tong, X.; Venkatraman, S.; Xia, E.; Girijavallabhan, V.; Njoroge, F. G. 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, 1013-1020.
29. For reviews about protease inhibitors, see: (a) Turk, B. Targeting Proteases: Successes, Failures and Future Prospects. Nat. Rev. Drug Discovery 2006, 5, 785-799.
30. (b) Tyndall, J. D.; Nall, T.; Fairlie, D. P. Proteases Universally Recognize Beta Strands in Their Active Sites. Chem. Rev. 2005, 105, 973-999.
31. (c) Powers, J. C.; Asgian, J. L.; Ekici, D.; James, K. E. Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases. Chem. Rev. 2002, 102, 4639-4643.
32. (d) Leung, D.; Abbenante, G.; Fairlie, D. P. Protease Inhibitors: Current Status and Future Prospects. J. Med. Chem. 2000, 43, 305-341.
33. 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-DTEDWP(Nva)-O-PAP was used in the present study..
34. i* and discussions, see: Morrison, J. F.; Walsh, C. T. In Advances in Enzymology and Related Areas of Molecular Biology Meister, A., Ed.; John Wiley & Sons, Inc., Hoboken, NJ, 1988; Vol 61, pp 201-301.
35. Schechter, I.; Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 1967, 27, 157-162.
36. 2′ α-Ketoamide Inhibitors of HCV NS3-NS4A Serine Protease: Effect on HCV Replicon Activity. Bioorg. Med. Chem. Lett. 2006, 16, 1621-1627.
37. Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu, Y.-T.; Lovey, R. G.; Venkatraman, S.; Pan, W.; Parekh, T.; Pike, R. E.; Ruan, S.; Liu, R.; Baroudy, B.; Agrawal, S.; Ingravallo, P.; Pichardo, J.; Prongay, A.; Brisson, J.-M.; Hsieh, T. Y.; Cheng, K.-C.; Kemp, S. J.; Levy, O. E.; Lim-Wilby, M.; Tamura, S. Y.; Saksena, A. K.; Girijavallabhan, V.; Njoroge, F. G. Discovery of SCH 446211(SCH6): A New Ketoamide Inhibitor of the HCV NS3 Serine Protease and HCV Subgenomic RNA Replication NS3 Serine. J. Med. Chem. 2006, 49, 2750-2757.
38. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.
39. Chen, K. X.; Njoroge, F. G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.; 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.
40. Velazquez, F.; Venkatraman, S.; Wu, W.; Blackman, M.; Prongay, A.; Girijavallabhan, V.; Shih, N.-Y.; Njoroge, F. G. Application of Ring-Closing Metathesis for the Synthesis of Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease. Org. Lett. 2007, 9, 3061-3064.