Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

Medchemcomm. 2012 Mar 1;(3):379-384. doi: 10.1039/C2MD00288D.

Abstract

The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other cardiovascular disorders. Piperazino functionality as the tertiary pharmacophore remarkably improved the drug-like profile of the 1,3-disubstituted urea sEH inhibitors. However, the potency was more dependent on the overall best balance of the hydrophilicity and lipophilicity. Based on the sEH-inhibitor complex structure, further structural optimization on the piperazino-containing 1,3-disubstituted urea scaffold was conducted for an improved potency. The 1-adamantylacetamide and para-phenylcarbonyl group were identified to be an optimal primary pharmacophore and secondary pharmacophore motif, respectively, generating sub-nanomolar sEH inhibitors with favorable water solubility.

Keywords: 1,3-disubstituted urea; 1-adamantylacetamide; EETs; piperazine; soluble epoxide hydrolase inhibitor.