17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analogues

J R Falck, Gerd Wallukat, Narender Puli, Mohan Goli, Cosima Arnold, Anne Konkel, Michael Rothe, Robert Fischer, Dominik N. Müller, Wolf Hagen Schunck

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

17(R),18(S)-Epoxyeicosatetraenoic acid [17(R),18(S)-EETeTr], a cytochrome P450 epoxygenase metabolite of eicosapentaenoic acid (EPA), exerts negative chronotropic effects and protects neonatal rat cardiomyocytes against Ca 2+-overload with EC50 ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ11,12- or Δ14,15- olefin and a 17(R),18(S)-epoxide are minimal structural elements for antiarrhythmic activity whereas antagonist activity was often associated with the combination of a Δ14,15-olefin and a 17(S),18(R)-epoxide. Compared with natural material, the agonist and antagonist analogues are chemically and metabolically more robust and several show promise as templates for future development of clinical candidates.

Original languageEnglish (US)
Pages (from-to)4109-4118
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number12
DOIs
StatePublished - Jun 23 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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