In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

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• 作者：Franois Maltais ; Young Chun Jung ; Minzhang Chen ; Jerry Tanoury ; Robert B. Perni ; Nagraj Mani ; Leena Laitinen ; Hui Huang ; Shengkai Liao ; Hongying Gao ; Hong Tsao ; Eric Block ; Chien Ma ; Rebecca S. Shawgo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 24, 2009
• 年：2009
• 卷：52
• 期：24
• 页码：7993-8001
• 全文大小：866K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

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 α-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 13% increase of AUC for 1.