Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease

VX-950 is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS34A serine protease, and it demonstrated excellent antiviral activity both in genotype 1b HCV replicon cells (50% inhibitory concentration [IC50] = 354 nM) and in human fetal hepatocytes infected with genotype la HCV-positive patient sera (IC50 = 280 nM). VX-950 forms a covalent but reversible complex with the genotype la HCV NS34A protease in a slow-on, slow-off process with a steady-state inhibition constant (K-i*) of 7 nM. Dissociation of the covalent enzyme-inhibitor complex of VX-950 and genotype la HCV protease has a half-life of almost an hour. A > 4-log(10) reduction in the HCV RNA levels was observed after a 2-week incubation of replicon cells with VX-950, with no rebound of viral RNA observed after withdrawal of the inhibitor. In several animal species, VX-950 exhibits a favorable pharmacokinetic profile with high exposure in the liver. In a recently developed FCV protease mouse model, VX-950 showed excellent inhibition of HCV NS34A protease activity in the liver. Therefore, the overall preclinical profile of VX-950 supports its candidacy as a novel oral therapy against hepatitis C.