Drugs in the PipelineOrally Active Epoxyeicosatrienoic Acid AnalogsCampbell, William B. PhD*; Imig, John D. PhD*; Schmitz, James M. MD†; Falck, John R. PhD†Author Information *Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI; and †Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX. Reprints: William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (e-mail: [email protected]). Supported by grants from the National Institutes of Health (HL-83297, HL-111392 and DK-103616), the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee grant and Robert A. Welch Foundation (I-0011). The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: October 2017 - Volume 70 - Issue 4 - p 211-224 doi: 10.1097/FJC.0000000000000523 Buy Metrics Abstract 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. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.