In vitro and in vivo isotope effects with hepatitis C protease inhibitors: enhanced plasma exposure of deuterated telaprevir versus telaprevir in rats.
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCV(a)) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a approximately 13% increase of AUC for 1.
Maltais
François
F
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
Jung
Young Chun
YC
Chen
Minzhang
M
Tanoury
Jerry
J
Perni
Robert B
RB
Mani
Nagraj
N
Laitinen
Leena
L
Huang
Hui
H
Liao
Shengkai
S
Gao
Hongying
H
Tsao
Hong
H
Block
Eric
E
Ma
Chien
C
Shawgo
Rebecca S
RS
Town
Christopher
C
Brummel
Christopher L
CL
Howe
David
D
Pazhanisamy
S
S
Raybuck
Scott
S
Namchuk
Mark
M
Bennani
Youssef L
YL
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D002021:Buffers; D003903:Deuterium / Q000737:chemistry; D004285:Dogs; D004355:Drug Stability; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007553:Isotope Labeling; D009842:Oligopeptides / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002021:Buffers; D003903:Deuterium; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir