RESUMEN

Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.

Asunto(s)

Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Oxindoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Células A549 , Animales , Sitios de Unión , Dominio Catalítico , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Oxindoles/farmacología , Oxindoles/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Relación Estructura-Actividad