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

Item Type:	Article
Title:	17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues
Creators Name:	Falck, J.R. and Wallukat, G. and Puli, N. and Goli, M. and Arnold, C. and Konkel, A. and Rothe, M. and Fischer, R. and Mueller, D.N. and Schunck, W.H.
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-Delta(11,12)- or Delta(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 Delta(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.
Keywords:	Alkenes, Anti-Arrhythmia Agents, Arachidonic Acids, Binding Sites, Calcium, Cardiac Myocytes, Cultured Cells, Eicosanoid Receptors, Eicosapentaenoic Acid, Myocardial Contraction, Stereoisomerism, Structure-Activity Relationship, Animals, Newborn Animals, Rats, Wistar Rats
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	54
Number:	12
Page Range:	4109-4118
Date:	23 June 2011
Official Publication:	https://doi.org/10.1021/jm200132q
PubMed:	View item in PubMed

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