title: Comparative biotransformation of pyrazinone-containing corticotropin-releasing factor receptor-1 antagonists: minimizing the reactive metabolite formation.
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.
authors.affiliation: Departments of Biotransformation, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. xiaoliang.zhuo@bms.com
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hartz
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Vijay T
authors.initials: VT
authors.lastname: Ahuja
authors.forename: Vivekananda M
authors.initials: VM
authors.lastname: Vrudhula
authors.forename: John E
authors.initials: JE
authors.lastname: Leet
authors.forename: Stella
authors.initials: S
authors.lastname: Huang
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Shu
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D020723:Glucuronic Acid / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D008956:Models, Chemical; D015394:Molecular Structure; D011719:Pyrazines / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D000099052:CRF Receptor, Type 1
chemical_list: C547831:BMS 665053; D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D020723:Glucuronic Acid; D005978:Glutathione