Discovery of small-molecule inhibitors of HCV ns3-4A protease as potential therapeutic agents against HCV infection

Current Medicinal Chemistry

Volumn 12, Issue 20, 2005, Pages 2317-2342

  Chen, Shu Hui ^a   Tan, Seng Lai ^b  

^a WUXI APPTEC   (China)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

HCV infections; NS3 protease; NS3 protease inhibitors; Viral resistance; VX 950

Indexed keywords

2 OXOACID; ALDEHYDE DERIVATIVE; ALPHA KETOAMIDE DERIVATIVE; ANTIVIRUS AGENT; BORONIC ACID DERIVATIVE; CILUPREVIR; HEXAPEPTIDE; HYDROXYPROLINE; INTERFERON; KETONE DERIVATIVE; LACTAM DERIVATIVE; MACROCYCLIC COMPOUND; PEGINTERFERON; PROLINE DERIVATIVE; PROTEINASE INHIBITOR; PYRROLIDINE DERIVATIVE; RIBAVIRIN; SERINE PROTEINASE; SULFONAMIDE; TETRAPEPTIDE; TRIPEPTIDE; UNCLASSIFIED DRUG; VIRUS ENZYME; VX 950;

ANTIBIOTIC RESISTANCE; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; CLINICAL TRIAL; DISEASE ASSOCIATION; DRUG APPROVAL; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; DRUG STRUCTURE; DRUG TARGETING; DRUG USE; EPIDEMIC; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FAILURE; LIVER TRANSPLANTATION; MORBIDITY; MORTALITY; NONHUMAN; REVIEW; SIDE EFFECT; STRUCTURE ACTIVITY RELATION; VIRUS MUTATION; VIRUS REPLICATION;

ANIMALS; ANTIVIRAL AGENTS; CARRIER PROTEINS; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; VIRAL NONSTRUCTURAL PROTEINS; VIRAL PROTEINS;

EID: 24944472318     PISSN: 09298673     EISSN: None     Source Type: Journal    
DOI: 10.2174/0929867054864769     Document Type: Review

References (94)

1. Rosenberg, S. J. Mol. Biol., 2001, 313, 451.
2. Tan, SL.; Pause, A.; Shi, Y.; Sonenberg, N. Nat Rev Drug Disco., 2002, 1, 867.
3. Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M. J. Virol., 2000, 74, 2046.
4. De Francesco, R.; Neddermann, P.; Tomei, L.; Steinkuhler, C.; Gallinari, P.; Folgori, A. Sem. Liv. Dis., 2000, 20, 69.
5. Yao, N. H.; Reichert, P.; Taremi, S. S.; Prosise, W. W.; Weber, P. C. Structure, 1999, 7, 1353.
6. Foy, E.; Wang, C.; Sumpter, R. Jr.; Ikeda, M.; Lemon, S. M.; Gale, M. Jr. Science, 2003, 300, 1145.
7. Dymock, B. W.; Jones, P. S.; Wilson, F. X. Antiviral Chem. Chemother., 2000, 11, 79.
8. Ingallinella, P.; Fattori, D.; Altamura, S.; Steinkuhler, C.; Koch, U.; Cicero, D.; Bazzo, R.; Cortese, R.; Bianchi, E.; Pessi, A. Biochemistry, 2002, 41, 5483.
9. Zhang, R. M.; Durkin, J. P.; Windsor, W. T. Bioorg. Med. Chem. Lett., 2002, 12, 1005.
10. Bartenschlager, R.; Lohmann, V. Antiviral Res., 2001, 52, 1.
11. Lamarre, D.; Anderson, PC.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, 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.; St George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C. L.; Llinas-Brunet, M. Nature, 2003, 426, 186-189.
12. Llinas-Brunet, M.; Bailey, M. D.; Bolger, G.; Brochu, C.; Faucher, A. M.; Ferland, J. M.; Garneau, M.; Ghiro, E.; Gorys, V.; Grand-Maitre, C.; Halmos, T.; Lapeyre-Paquette, N.; Liard, F.; Poirier, M.; Rheaume, M.; Tsantrizos, Y. S.; Lamarre, D. J. Med. Chem., 2004, 47, 1605-1608.
13. Slater, M. J. Design and synthesis of pyrrolidine-5,5- trans-lactams as novel inhibitors of hepatitis C virus protease. Antiviral Research - 15th International Conference, Prague, Czech Rebublic (17-21 March 2002).
14. News Release from Vertex Pharmaceuticals, Inc. entitled "Vertex Pharmaceuticals Announces Advancement to Phase 1b Clinical Tiral for VX-950, an Investigational Oral Protease Inhibitor for the Treatment of Hepatitis C" (Nov. 8, 2004).
15. Wyss, DF.; Arasappan, A.; Senior, M. M.; Wang, Y. S.; Beyer, B. M.; Njoroge, F. G.; McCoy, M. A. J. Med. Chem., 2004, 47, 2486.
16. Hegde, V. R.; Pu, H.; Patel, M.; Das, P. R.; Butkiewicz, N.; Arreaza, G.; Gullo, V. P.; Chan, T. M. Bioorg. Med. Chem. Lett., 2003, 13, 2925.
17. Fukuda, K.; Vishnuvardhan, D.; Sekiya, S.; Hwang, J.; Kakiuchi, N.; Taira, K.; Shimotohno, K.; Kumar, P. K.; Nishikawa, S. Eur. J. Biochem., 2000, 267, 3685.
18. Kumar, P. K.; Machida, K.; Urvil, P. T.; Kakiuchi, N.; Vishnuvardhan, D.; Shimotohno, K.; Taira, K.; Nishikawa, S. Virology, 1997, 237, 270.
19. Wang, Q. M. & Heinz, B. A. Prog. Drug Res., 2000, 55, 1.
20. Tanji, Y., Hijikata, M., Satoh, S., Kaneko, T.; Shimotohno, K. J. Virol., 1995, 69, 1575.
21. Yang, S. H.; Lee, C. G.; Song, M. K.; Sung, Y. C. Virol., 2000, 268, 132.
22. Darke, P. L.; Jacobs, A. R.; Waxman, L.; Kuo, L. C. J. Biol. Chem., 1999, 274, 34511.
23. Perni, R. B.; Kwong, A. D. In: Progress in Medicinal Chemistry; King, F. D.; Oxford, A. W., Eds.; Elsevier Science, 2002, pp.215-255.
24. Combrink, K. Drugs, 2002, 5, 815.
25. Walker, M. P.; Appleby, T. C.; Zhong, W.; Lau, J. Y. N.; Hong, Z. Antiviral Chem. Chemother., 2003, 14, 1.
26. De Francesco, R.; Tomei, L.; Altamura, S.; Summa, V.; Migliaccio, G. Antiviral Res., 2003, 58, 1.
27. Tan, S-L.; Victor, F.; Chen, S. H. In Frontiers of Biotechnology & Pharmaceuticals; Reiner, Zhao, Chen, Guo, Eds.; Science Press: Beijing, 2004; Vol. 4, pp. 123-146.
28. Attwood, M. R.; Bennett, J. M.; Cambell, A. D.; Canning, G. G. M.; Carr, M. G.; Conway, E.; Dunsdon, R. M. et al. Antiviral Chem. Chemother., 1999, 10, 259.
29. Vertex PCT patent: WO 98/17679 (1998).
30. Perni, R. B.; Britt, S. D.; Court, J. C.; Courtney, L. F.; Deininger, D. D.; Farmer, L. J. et al. Bioorg. Med. Chem. Lett., 2003, 13, 4059.
31. Dunsdon, R. M.; Greening, J. R.; Jones, P. S.; Jordan, S.; Wilson, F. X. Bioorg. Med. Chem. Lett., 2000, 10, 1577.
32. Priestley, E. S.; De Lucca, I.; Ghavimi, B,; Erickson-Viitanen, S.; Decicco, C. P. Bioorg. Med. Chem. Lett., 2002, 12, 3199.
33. Priestley, E. S.; Decicco, C. P. Org. Lett., 2000, 2, 3095.
34. Glunz, P. W.; Douty, B. D.; Decicco, C. P. Bioorg. Med. Chem. Lett., 2003, 13, 785.
35. DuPont Pharmaceuticals PCT paent application: WO 2000/102424.
36. Zhang, X.; Schmitt, A. C.; Jiang, W.; Wasserman, Z.; Decicco, C. P. Bioorg. Med. Chem. Lett., 2003, 13, 1157.
37. Narjes, F.; Brunetti, M.; Colarusso, S.; Gerlach, B.; Koch, U.; Bisasiol, G.; Fattori, D.; De Francesco, R.; Matassa, V. G.; Steinkuhler, C. Biochemistry, 2000, 39, 1849.
38. Di Marco, S.; Rizzi, M.; Volpari, C.; Walsh, M. A.; Narjes, F.; Colarusso, S.; De Francesco, R.; Matassa, V. G.; Sollazzo, M. J. Biol. Chem., 2000, 275, 7152.
39. Colarusso, S.; Gerlach, B.; Koch, U.; Muraglia, E.; Conte, I.; Stansfield, I.; Matassa, V. G.; Narjes, F. Bioorg. Med. Chem. Lett., 2002, 12, 705.
40. Nizi, E.; Koch, U.; Ponzi, S.; Matassa, V. G.; Gardelli, C. Bioorg. Med. Chem. Lett., 2003, 12, 3325.
41. Beaulieu, P-L.; Llinas-Brunet, M. Curr. Med. Chem. Anti-Infective Agents, 2002, 1, 163
42. Llinas-Brunet, M.; Bailey, M.; Fazal, G.; Ghiro, E.; Gorys, V.; Goulet, S.; Halmos, T.; Maurice, R.; Poirier, M.; Poupart, M-A.; Rancourt, J.; Thibeault, D.; Wernic, D.; Lamarre, D. Bioorg. Med. Chem. Lett., 2000, 10, 2267.
43. Tsantrizos, Y. S.; Bolger, G.; Bonneau, P.; Cameron, D. R.; Goudreau, N.; Kukolj, G.; LaPlante, S. R.; Llinas-Brunet, M.; Nar, H.; Lamarre, D. Angew. Chem. Int. Ed., 2003, 42, 1356.
44. Boehringer Ingelheim International GMBH PCT patent: WO 2003/064456 A1 (Aug. 7, 2003).
45. Boehringer Ingelheim (Canada) LTD. PCT patent: WO 2003/064455 A2 (Aug. 7, 2003).
46. US patent: 6608027 (Aug. 19, 2003).
47. Narjes, H.; Yong, C. L.; Steinmann, G. Hepatology, 2002, 36 (Suppl. 4, Part 2), Abst. 800.
48. Benhamou, Y.; Hinrichsen, H.; Sentijens, R.; Reiser, M.; Manns, M. P.; Forns, X.; Avendano, C.; Cronlein, J.; Nehmiz, G, Steinmann, G. Hepatology, 2002, 36(4), 304A.
49. Faucher, A-M.; Bailey, M. D.; Beaulieu, P. L.; Brochu, C.; Duceppe, J-S.; Ferland, J-M.; Ghiro, E.; Gorys, V.; Halmos, T.; Kawai, S. H.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S.; Llinas-Brunet, M. Org. Lett., 2004, 6, 2901.
50. Goudreay, N.; Brochu, C.; Cameron, D. R.; Duceppe, J-S.; Faucher, A-M.; Ferland, J-M.; Grand-Maitre, C.; Poirier, M.; Simoneau, B.; Tsantrizos, Y. S. J. Org. Chem., 2004, 69, 6185.
51. Llinas-Brunet, M.; Bailey, M. D.; Bolger, G.; Brochu, C.; Faucher, A-M.; Ferland, J. M.; Garneau, M.; Ghiro, E.; Gorys, V.; Grand-Maitre, C.; Halmos, T.; Lapeyre-Paquette, N.; Liard, F.; Poirier, M.; Rheaume, M.; Tsantrizos, Y. S.; Lamarre, D. J. Med. Chem., 2004, 47, 1605.
52. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A-M.; Goudreau, N.; Kawai, S. H.; Kukoij, G.; Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M-A.; Rancourt, J.; Sentjens, R. E.; St. George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Welden, S. M.; Yong, C-L.; Llinas-Brunet, M. Nature, 2003, 426, 186.
53. Asselah, T.; Marcellin, P. J. Hepatology, 2004, 41, 178.
54. Slater, M. J.; Andrews, D. M.; Baker, G.; Bethell, S. S.; Carey, S.; Chaignot, H.; Clarke, B.; Coomber, B.; Ellis, M.; Good, A.; Gray, N.; Hardy, G.; Jones, P.; Mills, G.; Robinson, E. Bioorg. Med. Chem. Lett., 2002, 12, 3359.
55. Andrews, D. M.; Carey, S. J.; Chaignot, H.; Coomber, B. A.; Gray, N. M.; Hind, S. L.; Jones, P. S.; Mills, G.; Robinson, J. E.; Slater, M. J. Org. Lett., 2002, 4, 4475.
56. Andrews, D. M.; Jones, P. S.; Mills, G.; Hind, S. L.; Slater, M. J.; Trivedi, N.; Wareing, K. J. Bioorg. Med. Chem. Lett., 2003, 13, 1657.
57. Andrews, D. M.; Chaignot, H.; Coomber, B. A.; Good, A. C.; Hind, S. L.; Johnson, M. R.; Jones, P. S.; Mills, G.; Robinson, J. E.; Skarzynski, T.; Slater, M. J.; O'N Somers, D. Org. Lett., 2002, 4, 4479.
58. Andrews, D. M.; Cahignot, H. M.; Coomber, B. A.; Dowle, M. D.; Hind, S. L.; Johnson, M. R.; Jones, P. S.; Mills, G.; Patikis, A.; Pateman, T. J.; Robinson, J. E.; Slater, M. J.; Trivedi, N. Euro. J. Med. Chem., 2003, 38, 339.
59. Slater, M. J.; Amphlett, E. M.; Andrews, D. M.; Bamborough, P.; Carey, S. J.; Johnson, M. R.; Jones, P. S.; Mills, G.; Parry, N. R.; Somers, D. O'N.; Stewart, A. J.; Skarzynski, T. Org. Lett., 2003, 5, 4627.
60. 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.; Robinson, J. E.; Slater, M. J.; Trivedi, N. Org. Lett., 2003, 5, 4631.
61. Bennett, J. M.; Cammbell, A. D.; Campbell, A. J.; Car, M. G. et al. Bioorg. Med. Chem. Lett., 2001, 11, 355.
62. Han, W.; Hu, Z.; Jiang, X.; Decicco, C. P. Bioorg. Med. Chem. Lett., 2000, 10, 711.
63. Vertex Pharmaceuticals, Inc. US patent: US-6,265,380 (Jul. 24, 2001).
64. Perni, R. B.; Britt, S. D.; Chambers, S. P.; Court, J. C.; Courtney, L. F. et al. Presented at the 226th ACS National Meeting, New York, NY on Sep. 6, 2003. Abst# MEDI-98.
65. Perni, R. B.; Pitlik, J.; Britt, S. D.; Cottrell, K. M.; Court, J. C. Courtney, L. F. et al. Presented at the 226th ACS National Meeting, New York, NY on Sep. 6, 2003. Abst# MEDI-99.
66. Perni, R. B.; Pitlik, J.; Britt, S. D.; Court, J. J.; Courney, L. F.; Deininger, D. D.; Farmer, L. J.; Gates, C. A.; Harbeson, S. L.; Levin, R. B.; Lin, C.; Lin, K.; Moon, Y-C.; Luong, Y-P.; O'Malley, E. T.; Rao, B. G.; Thomson, J. A.; Tung, R. D.; Van Drie, J. H.; Wei, Y. Bioorg. Med. Chem. Lett., 2004, 14, 1441.
67. Perni, R. B.; Farmer, L. J.; Cottrell, K. M.; Court, J. J.; Courney, 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. Bioorg. Med. Chem. Lett., 2004, 14, 1939.
68. Eli Lilly and Company PCT patent application: WO 2002/018369 (Jul. 3, 2002).
69. Yip, Y.; Victor, F.; Lamar, J.; Johnson, R.; Wang, Q. M.; Barket, D.; Glass, J.; Jin, L.; Liu, L.; Venable, D.; Wakulchik, M.; Xie, C.; Heinz, B.; Villarreal, E.; Colacino, J.; Yumibe, N.; Tebbe, M.; Munroe, J.; Chen, S. H. Bioorg. Med. Chem. Lett., 2004, 14, 251.
70. Vertex PCT patent application: WO 2003/006490 A1 (Jan. 23, 2003).
71. Vertex PCT patent application: WO 2003/035060 (May 1, 2003).
72. Schering Plough PCT patent application: WO 2003/062228 A1 (Jul. 31, 2003).
73. Schering Plough PCT patent application: WO 2001/77113 A2 (Oct. 18, 2001).
74. Schering Plough PCT patent application: WO 2001/81325 A2 (Nov. 1, 2001).
75. Victor, F.; Lamar, J.; Snyder, N.; Yip, Y.; Guo, D.; Yumibe, N.; Johnson, R. B.; Wang, Q. M.; Glass, J. I.; Chen, S. H. Bioorg. Med. Chem. Lett., 2004, 14, 257.
76. Yip, Y.; Victor, F.; Lamar, J.; Johnson, R.; Wang, Q. M.; Glass, J. I.; Yumibe, N.; Wakulchik, M.; Munroe, J.; Chen, S. H. Bioorg. Med. Chem. Lett., 2004, 14, 5007.
77. Lamar, J.; Victor, F.; Snyder, N.; Johnson, R. B.; Wang, Q. M.; Glass, J. I.; Chen, S. H. Bioorg. Med. Chem. Lett., 2004, 14, 263.
78. Chen, S. H.; Lamar, J.; Yip, Y.; Victor, F.; Johnson, R. B.; Wang, Q. M.; Glass, J. I.; Heinz, B.; Colacino, J.; Guo, D.; Tebbe, M.; Munroe, J. E. Letters in Drug Design and Discovery, 2005, 2, 118.
79. Sun, D. X.; Liu, L.; Heinz, B.; Kolykhalov, A.; Lamar, J.; Johnson, R. B.; Wang, Q. M.; Yip, Y.; Chen, S. H. Bioorg. Med. Chem. Lett., 2004, 14, 4333.
80. Guo, D.; Lamar, J.; Victor, F.; Yip, Y.; Wang, Q. M.; Glass, J. I. Chen, S. H. To be submitted to Bioorg. Med. Chem. Lett. ( 2005).
81. Perni, R. B.; Chandorkar, G.; Chen, S. H.; Colacino, J.; Chaturvedi, P.; Courtney, L. F.; Decker, C.; Gates, C.; Harbeson, S. L.; Kwong, A. D.; Lin, C.; Lin, K.; Monroe, J. E.; Luong, Y-P.; Murkuo, M. A.; Pitlik, J.; Rao, G.; Tebbe, M.; Tung, R. D.; Thomson, J. A. "VX-950: The Discovery of an Inhibitor of the Hepatitis C NS3-4A Protease and a Potential HCV Therapeutic' AASLD Annual Meeting, Boston, MA, October 24-28, 2003.
82. Perni, R. B.; Byrn, R.; Chandorkar, G.; Chaturvedi, P. R.; Chen, S. H.; Colacino, J.; Courtney, L. F.; Decker, C. J.; Gates, C. A.; Harbeson, S. L.; Kalleri, G.; Kwong, A. D.; Lin, C.; Luong, Y-P.; Markland, W.; Munroe, J. E.; Rao, G.; Tebbe, M. J.; Tung, R. D.; Thompson, J. A.; Yumibe, N. "The Properties and Preclinical Profile of VX-950, an Orally Bioavailable Inhibitor of Hepatitis C NS3-4A Protease and a Potential HCV Therapeutic" International Meeting on Hepatitis C Virus and Related Viruses, Kyoto, Japan, December 2-6, 2003.
83. Perni, R. B.; Britt, S. D.; Chen, S. H.; Court, J. C.; Chandorkar, G.; Cottrell, K. M.; Courtney, L. F.; Deininger, D. D.; Farmer, L. J.; Gates, C. A.; Harbeson, S. L.; Lamar, J.; Lin, C.; Luong, Y-P.; Munroe, J. E.; Pitlik, J.; Rao, G.; Schairer, W. C.; Tebbe, M. J.; Thompson, J. A.; Tung, R. D.; Van Drie, J. H.; Wei, Y. "The Design of Inhibitors of the HCV NS3-4A Protease: The Identification of a Clinical Development Candidate, VX-950" Presented at the 29th National Medicinal Chemistry Symposium, Madison, Wisconsin, June 27-July 1, 2004.
84. Lin, C.; Luong, Y-P.; Rao, G.; Wei, Y.; Brennan, D.; Fulghum, J.; Frantz, D.; Hsiao, K.; Ma, S.; Maxwell, J.; Pitlik, J.; Perni, R. B.; Gates, C. A.; Kwong, A. D. "VX-950: a Novel Hepatitis C Virus NS34A Protease Inhibitor, Retains Potency Against BILN-2061 Resistant Mutants" Presented at the 54th Annual Meeting of AASLD, Boston, MA, October 24-28, 2003.
85. Lin, C.; Lin, K.; Luong, Y-P.; Rao, G.; Wei, Y-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. J. Biol. Chem., 2004, 279, 17508.
86. News Release from Vertex Pharmaceuticals, Inc.entitled "Vertex Pharmaceuticals Reports Completion of Dosing in the Phase Ia Clinical Study of VX-950, an Oral HCV Protease Inhibitor for the Treatment of Hepatitis C" (Sept. 7, 2004).
87. News Release from Vertex Pharmaceuticals, Inc.entitled "Vertex Pharmaceuticals Reports Positive Results from First-in-Human Study for VX-950, an Investigational Oral Protease Inhibitor for the Treatment of Hepatitis C" (Nov. 1, 2004).
88. Chu, H-M.; McNair, L.; Purdy, S. "Results of a Phase 1 Single Dose Escalation Study of the Hepatitis C Protease Inhibitor VX-950 in Healthy Volunteers" Presented at the 55th Annual Meeting of AASLD, Boston, MA, Oct. 29-Nov. 2, 2004.
89. BMS PCT patent application: WO 03/099316 A1 (Dec. 4, 2003).
90. BMS PCT patent application: WO 2004/032827 A2 (April 22, 2004).
91. BMS PCT patent application: WO 2004/04339 A2 (May 27, 2004)
92. Boehringer Ingelheim PCT patent application: WO 2004/037855 A1 (May 6, 2004).
93. For a recent review, see: Gordon, C. P.; Keller, P. A. J. Med. Chem., 2005, 48, 1.
94. News Release from Vertex Pharmaceuticals, Inc. entitled "Vertex Pharmaceuticals Reports that VX-950, an Investigational Oral Hepatitis C Protease Inhibitor, Displays Potent Antiviral Activity in Early Clinical Study" (May 10, 2005).