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Enzymatic Synthesis of Epoxidized Metabolites of Docosahexaenoic, Eicosapentaenoic, and Arachidonic Acids
Published on: June 28, 2019
Orally Active Epoxyeicosatrienoic Acid Analogs
William B Campbell1, John D Imig, James M Schmitz
1*Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI; and †Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX.
Epoxyeicosatrienoic acids (EETs) show therapeutic potential for cardiovascular and kidney diseases. Novel EET agonists demonstrate oral activity and efficacy in preclinical models, supporting clinical trial advancement.
Area of Science:
- Biochemistry
- Pharmacology
- Nephrology
Background:
- Epoxyeicosatrienoic acids (EETs) are biologically active lipids synthesized from arachidonic acid.
- EETs possess vasodilatory, anti-inflammatory, and organ-protective properties.
- Therapeutic application of EETs is limited by metabolic instability.
Purpose of the Study:
- To develop metabolically stable EET analogs with therapeutic potential.
- To evaluate the efficacy of novel EET agonists in preclinical models of cardiovascular and kidney diseases.
Main Methods:
- Synthesis of 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates.
- Pharmacokinetic and efficacy studies in preclinical rat models.
- Assessment of cardiovascular and renal effects in models of hypertension, ischemia-reperfusion injury, heart failure, and diabetic nephropathy.
Main Results:
- Developed orally active EET agonist analogs (EET-A, EET-B, EET-C22) with favorable pharmacokinetics.
- Demonstrated significant reduction in blood pressure and cardiac/renal injury in various hypertensive models.
- Showed protective effects against acute and chronic kidney injury, including diabetic nephropathy and cardiorenal syndrome.
Conclusions:
- Orally active EET agonists exhibit potent therapeutic effects in preclinical models of cardiovascular and kidney diseases.
- These findings support the advancement of EET analogs into human clinical trials for treating these conditions.
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