title: In vitro and in vivo isotope effects with hepatitis C protease inhibitors: enhanced plasma exposure of deuterated telaprevir versus telaprevir in rats.
abstract: 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.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139, USA.
authors.forename: François
authors.initials: F
authors.lastname: Maltais
authors.forename: Young Chun
authors.initials: YC
authors.lastname: Jung
authors.forename: Minzhang
authors.initials: M
authors.lastname: Chen
authors.forename: Jerry
authors.initials: J
authors.lastname: Tanoury
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
authors.forename: Nagraj
authors.initials: N
authors.lastname: Mani
authors.forename: Leena
authors.initials: L
authors.lastname: Laitinen
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Shengkai
authors.initials: S
authors.lastname: Liao
authors.forename: Hongying
authors.initials: H
authors.lastname: Gao
authors.forename: Hong
authors.initials: H
authors.lastname: Tsao
authors.forename: Eric
authors.initials: E
authors.lastname: Block
authors.forename: Chien
authors.initials: C
authors.lastname: Ma
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Shawgo
authors.forename: Christopher
authors.initials: C
authors.lastname: Town
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Brummel
authors.forename: David
authors.initials: D
authors.lastname: Howe
authors.forename: S
authors.initials: S
authors.lastname: Pazhanisamy
authors.forename: Scott
authors.initials: S
authors.lastname: Raybuck
authors.forename: Mark
authors.initials: M
authors.lastname: Namchuk
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
mesh_terms: 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
chemical_list: 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