The soluble epoxide hydrolase as a pharmaceutical target for hypertension

Abstract

The soluble epoxide hydrolase appears to be a promising target for the development of antihypertensive therapies based on a previously unexplored mechanism of action. Epoxide hydrolases are enzymes that add water to three membered cyclic ethers known as epoxides. The soluble epoxide hydrolase in mammalian systems (sEH) is a member of the alpha/beta-hydrolase fold family of enzymes and it shows a high degree of selectivity for epoxides of fatty acids. The regioisomeric epoxides of arachidonic acid or epoxyeicosanoids (EETs) are particularly good substrates. These EETs appear to be major components of the endothelium-derived hyperpolarizing factors (EDHFs). As such, EETs cause vasodilation and reduce blood pressure. The EETs also are strongly anti-inflammatory and analgesic. By inhibiting sEH, the increase in circulating EETs leads to a reduction in blood pressure in a number of animal models. Potent transition state mimic inhibitors have been developed for the sEH. Some of these sEH inhibitors (sEHIs) show nanomolar to picomolar potency and good pharmacokinetic properties. Because of their unique mode of action they show promise in treating hypertension while reducing problems with end organ failure, vascular inflammation and diabetes. Indeed, the anti-inflammatory properties of the sEHI may make them particularly suitable for treating hypertension in patients with other concomitant metabolic syndromes. They are more potent on a molar basis than most nonsteroidal anti-inflammatory drugs (NSAIDs) in reducing PGE2 in inflammation models, they strongly synergize with NSAIDs, and appear to ameliorate apparently unfavorable eicosanoid profiles associated with some cyclo-oxygenase-2 inhibitors.