Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases

Abstract

The cardiovascular effects of epoxyeicosatrienoic acids (EETs) include vasodilation, antimigratory actions on vascular smooth muscle cells and anti-inflammatory actions. These endogenous lipid mediators are broken down into diols by soluble epoxide hydrolase (sEH), and so inhibiting this enzyme would be expected to enhance the beneficial cardiovascular properties of EETs. sEH inhibitors (sEHIs) that are based on 1,3-disubstituted urea have been rapidly developed, and have been shown to be antihypertensive and anti-inflammatory, and to protect the brain, heart and kidney from damage. Although challenges for the future exist - including improving the drug-like properties of sEHIs and finding better ways to target sEHIs to specific tissues - the recent initiation of the first clinical trials of sEHIs has highlighted the therapeutic potential of these agents.

Figure 1. Therapeutic Targets of the Arachidonate Cascade

Three major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treatment of pain, inflammation and blood clotting and prostacyclin analogs are used to treat pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are used to treat asthma and allergies. Soluble epoxide hydrolase inhibitors that increase epoxyeicosatrienoic acid levels are being developed for the treatment of cardiovascular diseases and inflammation.

Figure 2. Soluble Epoxide Hydrolase Inhibitor (sEHI) Structures and Binding to the Enzymatic Pocket

Left Panel: A.) The early compound AUDA contains the central pharmacophore C that forms multiple hydrogen bonds in the enzyme catalytic site. The R₁ or left side of the molecule rests in a hydrophobic pocket of the sEH catalytic tunnel. The hydrophobic right side of AUDA was designed to mimic 14,15-EET. AUDA is a highly potent sEHI but must be formulated carefully for use in vivo. B.) TPAU is a potent sEHI illustrating that a polar secondary pharmacophore P 7-8 Å from from C increases solubility while maintaining potency. It uses a piperidine as a L or linker group between C and P. C.) AUCB (both trans and cis isomers are active) has an ether as P with a R₂ on the right side reaching toward the enzyme surface and mimicking the carboxylate of EETs. Both TPAU and AUCB are highly potent and have good oral availability and pharmacokinetic characteristics. AUCB is more generally potent across multiple species. Right Panel: Structure of sEH enzymatic pocket with bound sEHI.

Figure 3. Soluble Epoxide Hydrolase Inhibitor (sEHI) Anti-hypertensive and End Organ Protective Actions

A.) sEHI treatment given orally at the onset of hypertension induced by angiotensin infusion lowers blood pressure. B.) sEHI treatment when given after the development of hypertension induced by angiotensin infusion lowers blood pressure. C.) sEHI decreases renal injury in diabetic hypertensive Goto-Kakizaki rats independent of lowering blood pressure. D.) sEHI decreases brain injury associated with cerebral ischemia in stroke-prone spontaneously hypertensive rats (SHRSP) independent of lowering blood pressure. Figure adapted from data in references 79,80,109,117.