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

Adeniyi Michael Adebesin, Tim Wesser, Jonnalagadda Vijaykumar, Anne Konkel, Mahesh P. Paudyal, Janine Lossie, Chen Zhu, Christina Westphal, Narender Puli, Robert Fischer, Wolf Hagen Schunck, John R. Falck

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10124-10143
Number of pages20
JournalJournal of Medicinal Chemistry
Volume62
Issue number22
DOIs
StatePublished - Nov 27 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Adebesin, A. M., Wesser, T., Vijaykumar, J., Konkel, A., Paudyal, M. P., Lossie, J., Zhu, C., Westphal, C., Puli, N., Fischer, R., Schunck, W. H., & Falck, J. R. (2019). Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogues as Potential Clinical Antiarrhythmic Agents. Journal of Medicinal Chemistry, 62(22), 10124-10143. https://doi.org/10.1021/acs.jmedchem.9b00952