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Development of robust 17(R),18(S)-epoxyeicosatetraenoic acid (17,18-EEQ) analogs as potential clinical antiarrhythmic agents

Authors

  • A.M. Adebesin
  • T. Wesser
  • J. Vijaykumar
  • A. Konkel
  • M. Paudyal
  • J. Lossie
  • C. Zhu
  • C. Westphal
  • N. Puli
  • R. Fischer
  • W.H. Schunck
  • J. Falck

Journal

  • Journal of Medicinal Chemistry

Citation

  • J Med Chem 62 (22): 10124-10143

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.


DOI

doi:10.1021/acs.jmedchem.9b00952