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Metabolism of mammalian soluble epoxide hydrolase inhibitors: 1‐adamantyl‐1‐yl‐3‐dodecyl‐urea and its esters
Author(s) -
Watanabe Takaho,
Morisseau Christophe,
Tsai HsingJu,
Hammock Bruce
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.8
Subject(s) - metabolite , chemistry , epoxide hydrolase 2 , epoxide hydrolase , metabolism , microsome , biochemistry , microsomal epoxide hydrolase , enzyme , butyric acid , urea , epoxide , catalysis
In mammals, soluble epoxide hydrolase (sEH) is involved in the metabolism of both exogenous and endogenous epoxides. The modulation of endogenous lipid epoxides using sEH inhibitors has therapeutic benefits in both hypertensive and inflammatory conditions. Understanding the route of metabolism should provide information leading to the design of more potent inhibitors. Metabolism of the lead compound, 1‐adamantyl‐1‐yl‐3‐dodecyl‐urea (ADU) and its esters, were investigated. Several metabolites of ADU, such as ω‐hydroxylated and ω‐carboxylate, were found in hepatic microsomes. The ratio of ω‐0/ω‐1 oxidation of ADU in human microsomes was different from rat and mouse. AUDA, which was metabolite from ADU, was potent and metabolically stable inhibitor. To improve solubility, we designed ester compounds. These ester compounds were immediately metabolized to AUDA in hepatic microsomes. AUDA was further metabolized to final metabolite (butyric acid metabolite (β‐oxidation)) in mouse urine.