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) 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.
Perni
Robert B
RB
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA. robert_perni@vrtx.com
Almquist
Susan J
SJ
Byrn
Randal A
RA
Chandorkar
Gurudatt
G
Chaturvedi
Pravin R
PR
Courtney
Lawrence F
LF
Decker
Caroline J
CJ
Dinehart
Kirk
K
Gates
Cynthia A
CA
Harbeson
Scott L
SL
Heiser
Angela
A
Kalkeri
Gururaj
G
Kolaczkowski
Elaine
E
Lin
Kai
K
Luong
Yu-Ping
YP
Rao
B Govinda
BG
Taylor
William P
WP
Thomson
John A
JA
Tung
Roger D
RD
Wei
Yunyi
Y
Kwong
Ann D
AD
Lin
Chao
C
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012367:RNA, Viral / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012093:Replicon / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013379:Substrate Specificity
D009842:Oligopeptides; D012367:RNA, Viral; D015842:Serine Proteinase Inhibitors; C486464:telaprevir