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J Med Chem. 2011 Jun 23;54(12):4109-18. doi: 10.1021/jm200132q. Epub 2011 Jun 1.

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

Author information

1
Department of Biochemistry, University of Texas Southwestern, Dallas, Texas 75390, United States. j.falck@utsouthwestern.edu

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 EC(50) ≈ 1-2 nM. Structure-activity studies revealed that a cis-Δ(11,12)- or Δ(14,15)-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 Δ(14,15)-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.

PMID:
21591683
PMCID:
PMC3122156
DOI:
10.1021/jm200132q
[Indexed for MEDLINE]
Free PMC Article

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