TY - JOUR
T1 - 17(R),18(S)-Epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction
T2 - Structure-activity relationships and stable analogues
AU - Falck, J R
AU - Wallukat, Gerd
AU - Puli, Narender
AU - Goli, Mohan
AU - Arnold, Cosima
AU - Konkel, Anne
AU - Rothe, Michael
AU - Fischer, Robert
AU - Müller, Dominik N.
AU - Schunck, Wolf Hagen
PY - 2011/6/23
Y1 - 2011/6/23
N2 - 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.
AB - 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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U2 - 10.1021/jm200132q
DO - 10.1021/jm200132q
M3 - Article
C2 - 21591683
AN - SCOPUS:79959434105
SN - 0022-2623
VL - 54
SP - 4109
EP - 4118
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -