Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide. Nucleoside inhibitors of the viral RNA-dependent RNA-polymerase (NS5B) have been investigated for several decades as potential treatment, but many clinical studies were terminated due to observed toxicities. Previously, MRL discovered MK-0608, a novel adenosine nucleoside analog NS5B inhibitor, which exhibited potent inhibition in the biochemical (as a triphosphate) and cell-based HCV replicon assays and potent antiviral efficacy in the chimpanzee model.  However, studies of MK-0608 in preclinical species revealed significant tissue accumulation that posed safety concerns, which contributed to the termination of its development.  Based on a detailed understanding of the biochemical, metabolic and tissue distribution profile of MK-0608, novel analogs were designed to specifically address these issues while maintaining potent anti-viral activity.  The strategy, design, synthesis and biological evaluations of these nucleosides will be presented.

Creative medicinal chemistry solutions to complex metabolic and tissue distribution issues for the hepatitis C virus polymerase nucleoside inhibitor MK-0608

251st National Meeting (2016)

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