RESUMO
A novel class of tetrazole-derived Kv1.5 blockers is disclosed. In in vitro studies, several compounds had IC(50)s ranging from 180 to 550 nM. In vivo studies indicated that compounds 2f and 2j increased right atrial ERP about 40% without affecting ventricular ERP.
Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Tetrazóis/farmacologia , Tiazóis/farmacologia , Animais , Frequência Cardíaca/efeitos dos fármacos , Cinética , Modelos Moleculares , Relação Estrutura-Atividade , Suínos , Porco Miniatura , Tetrazóis/química , Tiazóis/químicaRESUMO
A novel class of tetrahydroindolone-derived semicarbazones has been discovered as potent Kv1.5 blockers. In in vitro studies, several compounds exhibited very good potency for blockade of Kv1.5. Compound 8i showed good selectivity for blockade of Kv1.5 vs hERG and L-type calcium channels. In an anesthetized pig model, compounds 8i and 10c increased atrial ERP about 28%, 18%, respectively, in the right atrium without affecting ventricular ERP.
Assuntos
Potencial Evocado Motor/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Semicarbazonas/química , Semicarbazonas/farmacologia , Animais , Canais de Cálcio Tipo L/farmacologia , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/farmacologia , Potencial Evocado Motor/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Testes Neuropsicológicos , Relação Estrutura-Atividade , SuínosRESUMO
A series of novel (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones were prepared and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation.
