In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats
| Autor: | Eric Block, Hui Huang, Minzhang Chen, Christopher Town, Scott A. Raybuck, Young Chun Jung, Francois Maltais, Chien Ma, Christopher L Brummel, Robert B. Perni, Hongying Gao, Rebecca S. Shawgo, Jerry Tanoury, David Howe, Nagraj Mani, Leena Laitinen, Shengkai Liao, Youssef L. Bennani, Hong Tsao, S Pazhanisamy, Mark N. Namchuk |
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| Rok vydání: | 2009 |
| Předmět: |
Serine Proteinase Inhibitors
medicine.medical_treatment Hepatitis C virus Administration Oral Hepacivirus Buffers Viral Nonstructural Proteins Pharmacology medicine.disease_cause Antiviral Agents Telaprevir Dogs Drug Stability Pharmacokinetics In vivo Drug Discovery medicine Animals Humans Protease inhibitor (pharmacology) Protease biology Chemistry Stereoisomerism Hydrogen-Ion Concentration Deuterium In vitro Rats Biochemistry Enzyme inhibitor Isotope Labeling Injections Intravenous biology.protein Molecular Medicine Oligopeptides medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 52:7993-8001 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm901023f |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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