Non-urea functionality as the primary pharmacophore in soluble epoxide hydrolase inhibitors

Inhibition of soluble epoxide hydrolase has been proposed as a promising new pharmaceutical target for diseases involving hypertension and vascular inflammation. The most potent sEH inhibitors reported to date contain a urea or amide moiety as the central or ‘primary’ pharmacophore. We evaluated replacing the urea pharmacophore with other functional groups such as thiourea, sulfonamide, sulfonylurea, aminomethylene amide, hydroxyamide, and ketoamide to identify novel and potent inhibitors. The hydroxyamide moiety was identified as a novel pharmacophore affording potency comparable to urea.

Graphical abstractInhibition of soluble epoxide hydrolase (sEH) has been proposed as a promising new pharmaceutical target for diseases involving hypertension and vascular inflammation. We evaluated a number of non-urea primary pharmacophores based on the test scaffold 1 (P1 = NHCONH) which led to the discovery of hydroxyamide analog 19d as a novel and potent sEH inhibitor.Figure optionsDownload full-size imageDownload as PowerPoint slide