☆ 4.7 Article

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

JOURNAL OF MEDICINAL CHEMISTRY (2009)

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JOURNAL OF MEDICINAL CHEMISTRY

卷 52, 期 24, 页码 7993-8001

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AMER CHEMICAL SOC

DOI: 10.1021/jm901023f

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Chemistry, Medicinal

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Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) 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 similar to 13% increase of AUC for 1.

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