RESUMO
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.
Assuntos
Benzotiepinas/farmacologia , Benzoxazóis/farmacologia , Cardiotônicos/farmacologia , Condutividade Elétrica , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Animais , Benzotiepinas/síntese química , Benzotiepinas/química , Benzotiepinas/uso terapêutico , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/uso terapêutico , Cardiotônicos/síntese química , Cardiotônicos/química , Cardiotônicos/uso terapêutico , Linhagem Celular , Feminino , Cobaias , Humanos , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Ratos , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/uso terapêutico , Relação Estrutura-Atividade , Suínos , Fatores de TempoRESUMO
We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.