PT  - JOURNAL ARTICLE
AU  - Cheri M. Maciolek
AU  - Bennett Ma
AU  - Karsten Menzel
AU  - Sebastien Laliberte
AU  - Kevin Bateman
AU  - Paul Krolikowski
AU  - Christoper R. Gibson
TI  - Novel Cytochrome P450-Mediated Ring Opening of the 1,3,4-Oxadiazole in Setileuton, a 5-Lipoxygenase Inhibitor
AID  - 10.1124/dmd.110.037366
DP  - 2011 May 01
TA  - Drug Metabolism and Disposition
PG  - 763--770
VI  - 39
IP  - 5
4099  - http://dmd.aspetjournals.org/content/39/5/763.short
4100  - http://dmd.aspetjournals.org/content/39/5/763.full
SO  - Drug Metab Dispos2011 May 01; 39
AB  - 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.