Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) openers: benzopyranyl indoline and indole analogues

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (KATP) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 μM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial KATP blocker, indicating its provable protective mechanism through the mitochondrial KATP opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure–activity relationships in this series of compounds. [Copyright &y& Elsevier]