Abstract
(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0–7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.
Footnotes
↵1 Current affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028910
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- CRF
- corticotropin-releasing factor
- CRF-R1
- corticotropin-releasing factor receptor-1
- CRF-R2
- corticotropin-releasing factor receptor-2
- HPA
- hypothalamic-pituitary-adrenal
- BMS-665053
- (S)-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1H)-one
- HPLC
- high-performance liquid chromatography
- MS
- mass spectrometry
- PDA
- photodiode array
- amu
- atomic mass units
- MS/MS
- tandem mass spectrometry
- P450
- cytochrome P450
- HLM
- human liver microsome
- RLM
- rat liver microsome
- GGT
- γ-glutamyl transpeptidase.
- Received June 18, 2009.
- Accepted October 8, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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