Orally Active Epoxyeicosatrienoic Acid Analogs. J Cardiovasc Pharmacol 2017 Oct;70(4):211-224
Date
09/25/2017Pubmed ID
28937442Pubmed Central ID
PMC5673125DOI
10.1097/FJC.0000000000000523Scopus ID
2-s2.0-85032230771 (requires institutional sign-in at Scopus site) 45 CitationsAbstract
Biologically active epoxyeicosatrienoic acid (EET) regioisomers 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 after 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 preclinical 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 antiremodeling 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 preclinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.
Author List
Campbell WB, Imig JD, Schmitz JM, Falck JRAuthor
William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAdministration, Oral
Animals
Blood Pressure
Cardiovascular Diseases
Fatty Acids, Monounsaturated
Humans
Hypertension
Kidney Diseases
Muscle, Smooth, Vascular
Structure-Activity Relationship
Vasodilation
