Document Detail

Na+ currents in cardioprotection: better to be late.
MedLine Citation:
PMID:  19514733     Owner:  NLM     Status:  MEDLINE    
We report the discovery of a selective, potent inhibitor of the late current mediated by the cardiac isoform of the sodium channel (Na(V)1.5). The compound, 3,4-dihydro-N-[(2S)-3-[(2-hydroxy-3-methylphenyl)thio]-2-methylpropyl]-2H-(3R)-1,5-benzoxathiepin-3-amine (2d) (F 15741), blocks the late component of the Na(+) currents and greatly reduces veratridine- or ischemia-induced contracture in isolated tissue and whole heart. The cardioprotective action of 2d was further established in a model of myocardial infarction in the pig in which 2d prevents ischemia-reperfusion damage after 60 min of coronary occlusion and 48 h reperfusion. Under these experimental conditions, only 2d and cariporide reduce infarct size. Remarkably, myocardial protection afforded by 2d occurs in the absence of hemodynamic effects. These data expand the therapeutic potential of late I(Na) blockers and suggest that 2d could be useful in pathologies for which pharmacological treatments are not yet available.
Bruno Le Grand; Christophe Pignier; Robert Létienne; Francis Colpaert; Florence Cuisiat; Françoise Rolland; Agnes Mas; Maud Borras; Bernard Vacher
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-16     Completed Date:  2009-08-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4149-60     Citation Subset:  IM    
Pierre Fabre Research Center, 81106 Castres Cedex, France.
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MeSH Terms
Benzothiepins / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Benzoxazoles / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Cardiotonic Agents / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Cell Line
Electric Conductivity*
Guinea Pigs
Myocardial Infarction / drug therapy,  metabolism,  pathology,  physiopathology
Sodium Channel Blockers / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Sodium Channels / metabolism*
Structure-Activity Relationship
Time Factors
Reg. No./Substance:
0/3,4-dihydro-N-(3-((2-hydroxy-3-methylphenyl)thio)-2-methylpropyl)-2H-1,5-benzoxathiepin-3-amine; 0/Benzothiepins; 0/Benzoxazoles; 0/Cardiotonic Agents; 0/Sodium Channel Blockers; 0/Sodium Channels

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

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