Orally Active Epoxyeicosatrienoic Acid Analogs

Abstract

Biologically active epoxyeicosatrienoic acid regioisomers (EETs) are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size following ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In pre-clinical rat models, a subset of agonist analogs, termed EET-A, EET-B and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac anti-remodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling pre-clinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…Epoxyeicosatrienoic acids (EETs) are eicosanoids produced from arachidonic acid by cytochrome P450 (CYP) epoxygenases that have anti-inflammatory, anti-apoptotic, proangiogenic, and vasodilatory actions (Campbell et al, 2017). They are formed by a wide number of cells types relevant to cardiovascular, renal, and cerebral pathologies, most notably by arterial and venous endothelial cells.…”

“…These results suggest that TPPU delivery might be useful as an adjunct therapy for neuroprotection from reperfusion in patients undergoing thrombolysis or thrombectomy. Concurrent with the development of improved sEH inhibitors, has been the synthesis of orally active EET analogs with enhanced biological potency and half-life, attributable in some cases to inhibition of sEH activity (Campbell et al, 2017). The efficaciousness of these third generation EET analogs in preventing ischemic stroke injury awaits investigation.…”

A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

“…Compared to the extensive studies on designing and using sEH inhibitors, 35,62 the development of metabolically robust EET analogues feasible for in vivo application is only at the beginning. [32][33][34]63 A potential advantage of EET analogues is that they directly compensate for an EET deficiency. 36 In contrast, the beneficial effects of sEH inhibitors largely depend on endogenous EET production and, thus, on the expression and activity of CYP epoxygenases under the given pathological conditions.…”

“…21 EET-mediated prevention of hypoxia/reoxygenation-induced apoptosis and cell death has been demonstrated in endothelial cells and cardiomyocytes. [32][33][34][35][36] In the present study, we tested the hypothesis that synthetic EET analogues may protect the kidney against I/R-induced AKI. [25][26][27][28] Induction or transgenic overexpression of EET-generating CYP enzymes attenuated renal injury in rat and mouse models of angiotensin II-induced hypertension.…”

“…31 SEH-inhibitors and most recently also metabolically robust synthetic EET analogues are under development that may provide novel therapeutic options for the treatment of cardiovascular and renal disease. [32][33][34][35][36] In the present study, we tested the hypothesis that synthetic EET analogues may protect the kidney against I/R-induced AKI. Experiments were performed in uninephrectomized Lewis rats, a model that partially mimics the situation after renal transplantation.…”