title: Novel cytochrome P450-mediated ring opening of the 1,3,4-oxadiazole in setileuton, a 5-lipoxygenase inhibitor.
abstract: Setileuton [4-(4-fluorophenyl)-7-[({5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-1-benzopyran-2-one] is a selective inhibitor of the 5-lipoxygenase enzyme, which is under investigation for the treatment of asthma and atherosclerosis. During the development of setileuton, a metabolite (M5) was identified in incubations with rat, dog, and human liver microsomes that represented the addition of 18 Da to the 1,3,4-oxadiazole portion of the molecule. Based on mass spectral data, a ring opened structure was proposed and confirmed through comparison with a synthetic standard. The metabolic ring opening was examined in vitro in rat liver microsomes and was determined to be mediated by cytochrome P450s (P450s). Upon examination of the specific P450s involved using cDNA-expressed rat P450s, it was shown that CYP1A2 likely was the major isoform contributing to the formation of M5. Studies using stable labeled molecular oxygen and water demonstrated that the oxygen was incorporated from molecular oxygen, rather than water, and confirmed that the metabolic formation was oxidative. An alternative, comparatively slow pathway of chemical hydrolysis also was identified and described. Three potential mechanisms for the two-step metabolic ring opening of the 1,3,4-oxadizole are proposed.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, WP75A-203, P.O. Box 4, West Point, PA 19486, USA. Cheri_Maciolek@merck.com
authors.forename: Cheri M
authors.initials: CM
authors.lastname: Maciolek
authors.forename: Bennett
authors.initials: B
authors.lastname: Ma
authors.forename: Karsten
authors.initials: K
authors.lastname: Menzel
authors.forename: Sebastien
authors.initials: S
authors.lastname: Laliberte
authors.forename: Kevin
authors.initials: K
authors.lastname: Bateman
authors.forename: Paul
authors.initials: P
authors.lastname: Krolikowski
authors.forename: Christoper R
authors.initials: CR
authors.lastname: Gibson
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy; D050197:Atherosclerosis / Q000188:drug therapy; D003374:Coumarins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D010069:Oxadiazoles / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
chemical_list: D003374:Coumarins; D016859:Lipoxygenase Inhibitors; D010069:Oxadiazoles; C568910:setileuton; D003577:Cytochrome P-450 Enzyme System; D001094:Arachidonate 5-Lipoxygenase