Synthesis and biological evaluation of soluble epoxide hydrolase (sEH) inhibitors: t‐AUCB and its derivatives

Abstract

Soluble epoxide hydrolase (sEH, EC ) is involved in the metabolism of endogenously derived fatty acid epoxides, such as arachidonic acid, linoleic acid, and other lipid epoxides. Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase products of arachidonic acid, are known modulators of blood pressure and inflammation. A series of N,N′‐disubstituted ureas having a conformationally restricted cis‐ or trans‐1,4‐cyclohexane alpha to the urea were prepared and tested as sEH inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans‐isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. Among them, trans‐4‐[4‐(3‐Adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB, IC50 = 1.3 ± 0.05 nM) had excellent oral bioavailability (98%, n = 3) and blood area under the curve (AUC) in dogs and was effective in vivo to treat hypotension in lipopolysaccharide (LPS) challenged murine models. The synthesis, SAR, and PK properties of this series as well as the scale‐up process and efficacy of t‐AUCB along with PK profile of corresponding esters and salts of t‐AUCB also will be presented.(supported in part by NIEHS grant ES02710, NIEHS Superfund grant P42 ES04699, and NIEHS Center grant P30 ES05707)