17(R),18(S)-Epoxyeicosatetraenoic Acid, a Potent Eicosapentaenoic Acid (EPA) Derived Regulator of Cardiomyocyte Contraction: Structure鈥揂ctivity Relationships and Stable Analogues

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• 作者：John R. Falck ; Gerd Wallukat ; Narender Puli ; Mohan Goli ; Cosima Arnold ; Anne Konkel ; Michael Rothe ; Robert Fischer ; Dominik N. Mu虉ller ; Wolf-Hagen Schunck
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4109-4118
• 全文大小：995K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

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 Ca²⁺-overload with EC₅₀ 鈮?1鈥? nM. Structure鈥揳ctivity studies revealed that a cis-螖^11,12- or 螖^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 螖^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.