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| 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., Wallukat, G., Puli, N., Goli, M., Arnold, C., Konkel, A., Rothe, M., Fischer, R., 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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