Application of a Deuterium Replacement Strategy to Modulate the Pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a Novel CRF1Antagonist
| Autor: | Bindi Sohal, Gareth Williams, Olivier Kretz, Joel Krauser, Franck Picard, Rowan Stringer, Jeffrey Mckenna |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Metabolic Clearance Rate Stereochemistry Metabolite Administration Oral Pharmaceutical Science Receptors Corticotropin-Releasing Hormone Rats Sprague-Dawley chemistry.chemical_compound Pharmacokinetics In vivo Kinetic isotope effect Animals Humans Oxazoles Oxazole Pharmacology Molecular Structure Antagonist Hydrogen Bonding Metabolism Deuterium Rats chemistry Injections Intravenous Microsomes Liver Microsome Pyrazoles Protons |
| Zdroj: | Drug Metabolism and Disposition. 42:954-962 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.114.057265 |
| Popis: | Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist. In an attempt to suppress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for NVS-CRF38 and deuterated NVS-CRF38. In vitro kinetic isotope effects (KH/KD) were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ∼7) compared with the substrate depletion method (KH/KD ∼2). In vivo isotope effects were measured in rats after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes, isotope effects calculated from in vivo CLint corresponding to all biotransformation pathways were lower (KH/KD ∼2) compared with CLint values calculated from the O-demethylation reaction alone (KH/KD ∼7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected, a marked reduction of the O-demethylated metabolite was observed for NVS-CRF38; however, levels of NVS-CRF38's other metabolites increased, compensating to some extent for the isotope effect. |
| Databáze: | OpenAIRE |
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