Design, synthesis, and structure-activity relationships of novel imidazo[4,5-c]pyridine derivatives as potent non-nucleoside inhibitors of hepatitis C virus NS5B

Abstract

The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC₅₀ of 1.163 nM and a CC₅₀ >200 nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase.

Keywords: Genotype 1b; Hepatitis C virus; NS5B polymerase; Non-nucleoside inhibitor.