Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogs as Potential Clinical Antiarrhythmic Agents

Abstract

17(<i>R</i>),18(<i>S</i>)-Epoxyeicosatetraenoic acid (EEQ) is a cytochrome P450 metabolite of eicosapentaenoic acid (EPA) and a powerful negative chronotrope with low nanomolar activity in a neonatal rat cardiomyocyte (NRCM) arrhythmia model. Prior studies identified oxamide <b>2b</b> as a soluble epoxide hydrolase (sEH) stable replacement but unsuitable for <i>in vivo</i> applications due to limited oral bioavailability and metabolic stability. These ADME limitations have been addressed in an improved generation of negative chronotropes, e.g., <b>4</b> and <b>16</b>, which were evaluated as potential clinical candidates.