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

doi:10.1021/jm200132q

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

Biochemistry

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50 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-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.

Original language	English (US)
Pages (from-to)	4109-4118
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	12
DOIs	https://doi.org/10.1021/jm200132q
State	Published - Jun 23 2011

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm200132q

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Falck, J. R., Wallukat, G., Puli, N., Goli, M., Arnold, C., Konkel, A., Rothe, M., Fischer, R., Müller, D. N., & Schunck, W. H. (2011). 17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analogues. Journal of Medicinal Chemistry, 54(12), 4109-4118. https://doi.org/10.1021/jm200132q

17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction : Structure-activity relationships and stable analogues. / Falck, J R; Wallukat, Gerd; Puli, Narender; Goli, Mohan; Arnold, Cosima; Konkel, Anne; Rothe, Michael; Fischer, Robert; Müller, Dominik N.; Schunck, Wolf Hagen.

In: Journal of Medicinal Chemistry, Vol. 54, No. 12, 23.06.2011, p. 4109-4118.

Research output: Contribution to journal › Article › peer-review

Falck, JR, Wallukat, G, Puli, N, Goli, M, Arnold, C, Konkel, A, Rothe, M, Fischer, R, Müller, DN & Schunck, WH 2011, '17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: Structure-activity relationships and stable analogues', Journal of Medicinal Chemistry, vol. 54, no. 12, pp. 4109-4118. https://doi.org/10.1021/jm200132q

Falck, J R ; Wallukat, Gerd ; Puli, Narender ; Goli, Mohan ; Arnold, Cosima ; Konkel, Anne ; Rothe, Michael ; Fischer, Robert ; Müller, Dominik N. ; Schunck, Wolf Hagen. / 17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction : Structure-activity relationships and stable analogues. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 12. pp. 4109-4118.

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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.",

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

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