Structure-based optimization of cyclopropyl urea derivatives as potent soluble epoxide hydrolase inhibitors for potential decrease of renal injury without hypotensive action

Abstract

Epoxyeicosatrienoic acids (EETs) are known to have beneficial pharmacological effects on various cardiovascular events. However, EETs are biologically metabolized by soluble epoxide hydrolase (sEH) to less active metabolites. In our search for potent sEH inhibitors, we optimized a series of cyclopropyl urea derivatives and identified compound 38 as a potent sEH inhibitor with minimal CYP inhibition and good oral absorption in rats. Administration of 38 to DOCA-salt rats suppressed urinary albumin and MCP-1 excretion without affecting systolic blood pressure.

Keywords: Cyclopropyl urea; DOCA-salt rat; Epoxyeicosatrienoic acids; Inhibitors; Renal protection; Soluble epoxide hydrolase.