876708-03-1

RO-9187 is excellent substrates for deoxycytidine kinase and is phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. It inhibits RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4′-azidocytidine) or 2′-C-methyl nucleosides. The formation of RO-9187-TP increased in a time- and dose-dependent manner. The maximal triphosphate concentration at 24 h is 87 pmol/106 cells with half-maximal triphosphate formation achieved at 12 μM RO-9187.

Plasma exposures of RO-9187 in rats increase in a dose-dependent manner between 10 and 2000 mg/kg after oral dosing. Plasma concentrations of 1.4 and 26 μM (390 and 7454 ng/mL) are achieved in rats and dogs at the 10 mg/kg dose level, respectively. Plasma concentrations up to 57 μM are achieved in rats dosed with 2000 mg/kg/day.

IC50: 171 nM (HCV)