Document Detail


17(R),18(S)-epoxyeicosatetraenoic acid, a potent eicosapentaenoic acid (EPA) derived regulator of cardiomyocyte contraction: structure-activity relationships and stable analogues.
MedLine Citation:
PMID:  21591683     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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-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.
Authors:
John R Falck; Gerd Wallukat; Narender Puli; Mohan Goli; Cosima Arnold; Anne Konkel; Michael Rothe; Robert Fischer; Dominik N Müller; Wolf-Hagen Schunck
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-06-01
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  54     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-16     Completed Date:  2011-09-16     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4109-18     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alkenes / chemical synthesis*,  pharmacology
Animals
Animals, Newborn
Anti-Arrhythmia Agents / chemical synthesis*,  pharmacology
Arachidonic Acids / chemical synthesis*,  pharmacology
Binding Sites
Calcium / metabolism
Cells, Cultured
Eicosapentaenoic Acid / analogs & derivatives*,  chemical synthesis*,  pharmacology
Myocardial Contraction / drug effects*
Myocytes, Cardiac / drug effects*,  physiology
Rats
Rats, Wistar
Receptors, Eicosanoid / agonists,  antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
DK38226/DK/NIDDK NIH HHS; GM31278/GM/NIGMS NIH HHS; P01 DK038226/DK/NIDDK NIH HHS; P01 DK038226-25/DK/NIDDK NIH HHS; R01 GM031278/GM/NIGMS NIH HHS; R01 GM031278-27/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Alkenes; 0/Anti-Arrhythmia Agents; 0/Arachidonic Acids; 0/Receptors, Eicosanoid; 131339-23-6/17,18-epoxy-5,8,11,14-eicosatetraenoic acid; AAN7QOV9EA/Eicosapentaenoic Acid; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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