Development of combined soluble epoxide hydrolase inhibitors and epoxide analogs with vasodilator activity

Abstract

Epoxyeicosatrienoic acids (EET) and soluble epoxide hydrolase inhibitors (SEHi) possess cardiovascular protective properties. SEHi are currently being clinically tested for the treatment of hypertension and EET analogs have recently been demonstrated to possess anti‐hypertensive properties. Thus, a series of compounds were synthesized to have EET analog and SEHi activities. Two of these compounds had a low nM IC50 for SEH and possessed vasoactivity similar to 14,15‐EET in bovine coronary arteries. These two compounds were evaluated further in rat mesenteric resistance arteries. Rat mesenteric resistance arteries averaged 293 ± 6 um at 65 mmHg and were preconstricted with U46619 to 164 ± 5 um. Compound A and compound B dose‐dependently dilated the mesenteric resistance artery and this dilation reached 40% at a 10 uM. Compound A was more active and had a greater dilator effect on mesenteric resistance arteries at lower doses. On the other hand, compound B has a lower IC50 (46 nM) for the SEH enzyme. The EET antagonist, 14,15‐EEZE abolished the dilator responses to compound A and B demonstrating EET mimetic activity for the compounds. These data demonstrate the ability to synthesize dual SEHi / EET analogs and provide initial evidence for beneficial cardiovascular properties.