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Antimicrobial Agents and Chemotherapy, March 2006, p. 899-909, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.899-909.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease

Robert B. Perni,* 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, and Chao Lin*

Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139

Received 8 August 2005/ Returned for modification 4 October 2005/ Accepted 8 December 2005

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 (Ki*) 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.

* Corresponding author. Mailing address: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139. Phone for Robert B. Perni: (617) 444-6237. Fax: (617) 444-6766. E-mail: robert_perni{at}vrtx.com. Phone for Chao Lin: (617) 444-6202. Fax: (617) 444-6210. E-mail: chao_lin{at}vrtx.com.

Antimicrobial Agents and Chemotherapy, March 2006, p. 899-909, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.899-909.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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