Ureas derived from camphor and fenchone reveal enantiomeric preference of human soluble epoxide hydrolase

Abstract

The soluble epoxide hydrolase (sEH) is a potential target to treat cardiovascular, renal and neuronal diseases. A series of sEH inhibitors containing naturally occurring lipophilic groups (originating from camphor and fenchone) were developed. Inhibitory potency ranging from 0.7 nM to 6.47 μM was obtained. It was discovered that ureas derived from l-camphor were more active against sEH (2.3-fold average) than the corresponding analogues derived from d-camphor indicating enantiomeric preference of sEH. Ureas derived from fenchone possess lower activity against sEH (ca. 80-fold on average) than their camphor-derived analogs due to the specific structure of the lipophilic fragment and show less enantiomeric preference (1.75-fold on average). Moreover, fenchone-derived ureas show no consistency in enantiomeric preference. Endo/exo-form of compound L-3a derived from l-camphor is 4-fold more potent than the corresponding analogue prepared from d-camphor (IC50 = 0.7 nM vs 2.8 nM) making it the most promising sEH inhibitor among the tested series.

Keywords

• Soluble epoxide hydrolase
• Inhibitor
• Epoxyeicosatrienoic acids
• Urea
• Camphor
• Fenchone