Nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) have illustrated pan-genotype activity, a high barrier to the selection of resistance and the potential for potent antiviral activity. NIs tested clinically are all N-nucleoside derivatives. GS-6620 is a nucleotide prodrug of C-nucleoside analog. GS-6620 shows potent activity (EC50 of 67.8 to 427 nM in replicon assays for GT1a-6a) and a high barrier to resistance in vitro. The active triphosphate metabolite serves as a chain-terminator of RNA elongation by NS5B and is an effective inhibitor in enzymatic assays (IC50 of 0.29 �M (GT1b) and 0.39 �M (GT2a) and Ki/Km of 0.11 (GT1b)). Oral administration of GS-6620 to animals resulted in efficient delivery of the triphosphate metabolite into the liver. The chemical structure of GS-6620 will be disclosed for the first time.  In addition, SAR and Phase 1 clinical results will be presented.

Discovery of GS-6620: C-Nucleoside HCV polymerase inhibitor

244th National Meeting (2012)

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