An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Nature

Volumn 426, Issue 6963, 2003, Pages 186-189

  Lamarre, Daniel ^a   Anderson, Paul C ^a   Bailey, Murray ^a   Beaulieu, Pierre ^a   Bolger, Gordon ^a   Bonneau, Pierre ^a   Bös, Michael ^a   Cameron, Dale R ^a,e   Cartier, Mireille ^a   Cordingley, Michael G ^a   Faucher, Anne Marie ^a   Goudreau, Nathalie ^a   Kawai, Stephen H ^a   Kukolj, George ^a   Lagacé, Lisette ^a   LaPlante, Steven R ^a   Narjes, Hans ^b   Poupart, Marc André ^a   Rancourt, Jean ^a   Sentjens, Roel E ^c   St George, Roger ^d   Simoneau, Bruno ^a   Steinmann, Gerhard ^b   Thibeault, Diane ^a   Tsantrizos, Youla S ^a   Weldon, Steven M ^d   Yong, Chan Loi ^d   Llinàs Brunet, Montse ^a   more..

^a BOEHRINGER INGELHEIM CANADA LTD   (Canada)

^b BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^c ACADEMIC MEDICAL CENTER   (Netherlands)

^d BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

^e Migenix Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DISEASES; DRUG PRODUCTS; RNA; VIRUSES;

MORBIDITY; MORTALITY;

ENZYMES;

CILUPREVIR; NS3 PROTEASE INHIBITOR; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; VIRUS RNA;

HEPATITIS; MEDICINE;

ANTIVIRAL ACTIVITY; ARTICLE; BLOOD LEVEL; CLINICAL ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG POTENCY; DRUG SCREENING; DRUG SPECIFICITY; GENOTYPE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; INGESTION; MALE; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL;

ADMINISTRATION, ORAL; ANTIVIRAL AGENTS; CARBAMATES; DOUBLE-BLIND METHOD; HEPACIVIRUS; HEPATITIS C; HUMANS; MACROCYCLIC COMPOUNDS; MALE; POLYPROTEINS; PROTEIN PROCESSING, POST-TRANSLATIONAL; QUINOLINES; SERINE PROTEINASE INHIBITORS; THIAZOLES; VIRAL LOAD; VIRAL NONSTRUCTURAL PROTEINS; VIRAL PROTEINS;

HEPATITIS C VIRUS; RNA VIRUSES;

EID: 0344201903     PISSN: 00280836     EISSN: None     Source Type: Journal    
DOI: 10.1038/nature02099     Document Type: Article

References (30)

1. Choo, Q. L. et al. Isolation of a cDNA clone derived from a blood-borne non-A non-B viral hepatitis genome. Science 244, 359-362 (1989).
2. Kuo, G. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244, 362-364 (1989).
3. Di Bisceglie, A. M. Hepatitis C. Lancet 351, 351-355 (1998).
4. Chander, G. et al. Treatment of chronic hepatitis C: a systematic review. Hepatology 36, S135 (2002).
5. Tan, S.-L., Pause, A., Shi, Y. & Sonenberg, N. Hepatitis C therapeutics: current status and emerging strategies. Nature Rev. Drug Discov. 1, 867-881 (2002).
6. Di Bisceglie, A. M., McHutchison, J. & Rice, C. M. New therapeutic strategies for hepatitis C. Hepatology 35, 224-231 (2002).
7. Reed, K. E. & Rice, C. M. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr. Top. Microbiol. Immunol. 242, 55-84 (2000).
8. 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. 74, 2046-2051 (2000).
9. Lohmann, V. et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 103-107 (1999).
10. Mercer, D. F. et al. Hepatitis C virus replication in mice with chimeric human livers. Nature Med. 7, 927-933 (2001).
11. Schechter, I. & Berger, A. Protease subsite nomenclature. Biochem. Biophys. Res. Commun. 27, 157-162 (1967).
12. Llinàs-Brunet, M. et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 1713-1718 (1998).
13. Steinkühler, C. et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 37, 8899-8905 (1998).
14. Llinàs-Brunet, M. et al. Studies on the C-terminal of hexapeptide inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 2719-2724 (1998).
15. Llinàs-Brunet, M. et al. Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg. Med. Chem. Lett. 10, 2267-2270 (2000).
16. Poupart, M.-A. et al. Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease. J. Org. Chem. 66, 4743-4751 (2001).
17. Goudreau, N. et al. NMR structural characterization of peptide inhibitors bound to the HCV NS3 protease: design of a new P2 substituent. J. Med. Chem. (submitted).
18. Pause, A. et al. An NS3 serine protease inhibitor abrogates replication of subgenomic hepatitis C virus RNA. J. Biol. Chem. 278, 20374-20380 (2003).
19. LaPlante, S. R. et al. Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain. J. Biol. Chem. 274, 18618-18624 (1999).
20. LaPlante, S. R. et al. NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain. Bioorg. Med. Chem. Lett. 10, 2271-2274 (2000).
21. Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor tripeptides. US patent 6,323,180 B1 (2001).
22. Tsantrizos, Y. et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew. Chem. Int. Edn Engl. 42, 1356-1360 (2003).
23. Narjes, H., Yong, C. L., Stahle, H. & Steinmann, G. Tolerability and pharmacokinetics of BILN 2061: a novel serine protease HCV inhibitor after oral single doses of 5 mg to 2,400 mg in healthy male subjects. Hepatology 36(4), Abst. 800 (2002).
24. Hinrichsen, H. et al. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1. Hepatology 36, 297A, Abst. 866 (2002).
25. Benhamou, Y. et al. Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C, genotype 1, with advanced liver fibrosis. Hepatology 36, 304A, Abst. 563 (2002).
26. Neumann, A. U. et al. Hepatitis C viral dynamics in vivo the and antiviral efficacy of interferon-alpha therapy. Science 282, 103-107 (1998).
27. Neumann, A. U. et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J. Infect. Dis. 182, 28-35 (2000).
28. Zeuzem, S. et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha 2a. Gastroenterology 120, 1438-1447 (2001).
29. Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300, 1145-1148 (2003).
30. Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the Hepatitis C virus. US patent 6,608,027 B1 (2003).