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

J Med Chem. 2019 Nov 27;62(22):10124-10143. doi: 10.1021/acs.jmedchem.9b00952. Epub 2019 Nov 19.

Abstract

17(R),18(S)-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 2b as a soluble epoxide hydrolase (sEH) stable replacement but unsuitable for in vivo applications due to limited oral bioavailability and metabolic stability. These ADME limitations have been addressed in an improved generation of negative chronotropes, e.g., 4 and 16, which were evaluated as potential clinical candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Arrhythmia Agents / chemistry*
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / pharmacology*
  • Arachidonic Acids / chemistry*
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / metabolism
  • Esterification
  • Hepatocytes / drug effects
  • Humans
  • Male
  • Mice
  • Microsomes, Liver / drug effects
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / drug effects*
  • Rats, Sprague-Dawley
  • Rats, Wistar

Substances

  • Anti-Arrhythmia Agents
  • Arachidonic Acids
  • 17,18-epoxy-5,8,11,14-eicosatetraenoic acid
  • Epoxide Hydrolases