RESUMO
K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Função Atrial/efeitos dos fármacos , Benzopiranos/farmacologia , Canal de Potássio Kv1.5/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Função Atrial/fisiologia , Benzopiranos/química , Canal de Potássio Kv1.5/metabolismo , Modelos Químicos , Bloqueadores dos Canais de Potássio/síntese química , Sulfonamidas/químicaRESUMO
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents.
Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Mitocôndrias/enzimologia , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Animais , Bovinos , Inibidores Enzimáticos/síntese química , Guanidinas/síntese química , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Relação Estrutura-AtividadeRESUMO
Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
