Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3ß inhibitors.
Bioorg Med Chem
; 27(9): 1804-1817, 2019 05 01.
Article
em En
| MEDLINE
| ID: mdl-30902399
ABSTRACT
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 4.19â¯nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10⯵M 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 50â¯mg/kg body weight thus representing an interesting lead for further optimization.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Glicogênio Sintase Quinase 3 beta
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Oxindóis
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article