Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Gastroenterology & Hepatology, Non-nucleoside, HCV RdRp inhibitor, Combination, Viral clearance, CHRONIC HEPATITIS-C, HIGHLY SELECTIVE INHIBITOR, HCVNS5B POLYMERASE, RIBAVIRIN ANTAGONIZES, PROTEASE INHIBITOR, NONNUCLEOSIDE INHIBITORS, NUCLEOSIDE ANALOGS, ANTIVIRAL ACTIVITY, VIRUS-REPLICATION, CROSS-RESISTANCE, Antiviral Agents, Carcinoma, Hepatocellular, Cell Line, Tumor, Hepacivirus, Humans, Imidazoles, Interferons, Liver Neoplasms, Protease Inhibitors, Pyridines, RNA, Viral, Ribavirin, Virus Replication, 1103 Clinical Sciences, 1117 Public Health and Health Services, 3202 Clinical sciences

Abstract:

BACKGROUND/AIMS: Following lead optimization, a set of substituted imidazopyridines was identified as potent and selective inhibitors of in vitro HCV replication. The particular characteristics of one of the most potent compounds in this series (5-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine or GS-327073), were studied. METHODS: Antiviral activity of GS-327073 was evaluated in HCV subgenomic replicons (genotypes 1b, 1a and 2a), in the JFH1 (genotype 2a) infectious system and against replicons resistant to various selective HCV inhibitors. Combination studies of GS-327073 with other selective HCV inhibitors were performed. RESULTS: Fifty percent effective concentrations for inhibition of HCV subgenomic 1b replicon replication ranged between 2 and 50 nM and were 100-fold higher for HCV genotype 2a virus. The 50% cytostatic concentrations were > or = 17 microM, thus resulting in selectivity indices of > or = 340. GS-327073 retained wild-type activity against HCV replicons that were resistant to either HCV protease inhibitors or several polymerase inhibitors. GS-327073, when combined with either interferon alpha, ribavirin, a nucleoside polymerase or a protease inhibitor resulted in overall additive antiviral activity. Combinations containing GS-327073 proved highly effective in clearing hepatoma cells from HCV. CONCLUSIONS: GS-327073 is a potent in vitro inhibitor of HCV replication either alone or in combination with other selective HCV inhibitors.