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

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

  • Antimicrob Agents Chemother. 2006 Mar;50(3):899-909. doi: 10.1128/AAC.50.3.899-909.2006.
Robert B Perni 1,  Susan J Almquist,  Randal A Byrn,  Gurudatt Chandorkar,  Pravin R Chaturvedi,  Lawrence F Courtney,  Caroline J Decker,  Kirk Dinehart,  Cynthia A Gates,  Scott L Harbeson,  Angela Heiser,  Gururaj Kalkeri,  Elaine Kolaczkowski,  Kai Lin,  Yu-Ping Luong,  B Govinda Rao,  William P Taylor,  John A Thomson,  Roger D Tung,  Yunyi Wei,  Ann D Kwong,  Chao Lin
Affiliations

Affiliation

  • 1 Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA. robert_perni@vrtx.com
PMID: 16495249 DOI: 10.1128/AAC.50.3.899-909.2006
Abstract

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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