Abstract
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.
MeSH terms
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Animals
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Benzothiepins / chemical synthesis
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Benzothiepins / chemistry
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Benzothiepins / pharmacology*
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Benzothiepins / therapeutic use
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Benzoxazoles / chemical synthesis
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Benzoxazoles / chemistry
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Benzoxazoles / pharmacology*
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Benzoxazoles / therapeutic use
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Cardiotonic Agents / chemical synthesis
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Cardiotonic Agents / chemistry
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Cardiotonic Agents / pharmacology*
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Cardiotonic Agents / therapeutic use
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Cell Line
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Electric Conductivity*
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Female
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Guinea Pigs
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Humans
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Male
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Myocardial Infarction / drug therapy
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Rats
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Sodium Channel Blockers / chemical synthesis
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Sodium Channel Blockers / chemistry
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Sodium Channel Blockers / pharmacology*
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Sodium Channel Blockers / therapeutic use
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Sodium Channels / metabolism*
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Structure-Activity Relationship
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Swine
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Time Factors
Substances
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3,4-dihydro-N-(3-((2-hydroxy-3-methylphenyl)thio)-2-methylpropyl)-2H-1,5-benzoxathiepin-3-amine
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Benzothiepins
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Benzoxazoles
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Cardiotonic Agents
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Sodium Channel Blockers
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Sodium Channels