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Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. 2006
Robert B Perni, and
Susan J Almquist, and
Randal A Byrn, and
Gurudatt Chandorkar, and
Pravin R Chaturvedi, and
Lawrence F Courtney, and
Caroline J Decker, and
Kirk Dinehart, and
Cynthia A Gates, and
Scott L Harbeson, and
Angela Heiser, and
Gururaj Kalkeri, and
Elaine Kolaczkowski, and
Kai Lin, and
Yu-Ping Luong, and
B Govinda Rao, and
William P Taylor, and
John A Thomson, and
Roger D Tung, and
Yunyi Wei, and
Ann D Kwong, and
Chao Lin
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA. robert_perni@vrtx.com
VX-950 is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A 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 1a HCV-positive patient sera (IC50 = 280 nM). VX-950 forms a covalent but reversible complex with the genotype 1a HCV NS3-4A 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 1a HCV protease has a half-life of almost an hour. A >4-log10 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 HCV protease mouse model, VX-950 showed excellent inhibition of HCV NS3-4A protease activity in the liver. Therefore, the overall preclinical profile of VX-950 supports its candidacy as a novel oral therapy against hepatitis C.
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