RESUMO
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
In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.
Assuntos
Benzopiranos/síntese química , Cardiotônicos/síntese química , Imidazóis/síntese química , ATPases Mitocondriais Próton-Translocadoras/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/metabolismo , Animais , Benzopiranos/química , Benzopiranos/farmacologia , Cardiotônicos/química , Cardiotônicos/farmacologia , Bovinos , Citrato (si)-Sintase/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Hidrólise , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Ratos , Estereoisomerismo , 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.