RESUMO
Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.
Assuntos
Benzamidas/síntese química , Oxidiazóis/síntese química , Bloqueadores dos Canais de Potássio , Bloqueadores dos Canais de Potássio/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Desenho de Fármacos , Técnicas In Vitro , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Oócitos/metabolismo , Oócitos/fisiologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , XenopusAssuntos
Cardiotônicos/farmacologia , Miocárdio/metabolismo , Canais de Potássio/agonistas , Transportadores de Cassetes de Ligação de ATP , Animais , Cardiotônicos/química , Cães , Canais KATP , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Canais de Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.