In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea

1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU) is a potent soluble epoxide hydrolase (sEH) inhibitor that is used extensively for modulating inflammation and protecting against hypertension, neuropathic pain and neurodegeneration. Despite its wide use in various animal disease models, the metabolism of TPPU has not been well studied. Herein, we describe the identification of TPPU metabolites using LC-MS/MS strategies. Four metabolites (M1-M4) were identified from rat urine by a sensitive LC-MS/MS method with double precursor ion scans. Their structures were further supported by LC-MS/MS comparison with synthesized standards. M1 and M2 were formed from hydroxylation on a propionyl group; M3 was formed by amide hydrolysis of the 1-propionylpiperdinyl group; and M4 was formed by further oxidation of M2. Interestingly, the predicted -diketone metabolite and 4-(trifluoromethoxy)aniline (formed from urea cleavage) were not detected by LC-MRM-MS method. This indicates that if formed, the two potential metabolites represent
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research