Synthesis and biological evaluation of 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as potent, selective GSK-3ß inhibitors and neuroprotective agents.
Bioorg Med Chem
; 23(5): 1179-88, 2015 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-25662701
ABSTRACT
A series of novel 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides were designed, prepared and evaluated for their GSK-3ß inhibitory activities. Most compounds showed high potency to GSK-3ß inhibition with high selectivity. Among them, compounds 7c, 7f, 7h, 7l and 7m significantly reduced GSK-3ß substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3ß. In the in vitro neuronal injury models, compounds 7c, 7f, 7h, 7l and 7m prevented neuronal death against glutamate, oxygen-glucose deprivation and nutrient serum deprivation which are associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 7f reduced infarct size by 15% and improved the neurological deficit following focal cerebral ischemia. These findings may provide new insights into the development of novel GSK-3ß inhibitors with potential neuroprotective activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
/
Quinase 3 da Glicogênio Sintase
/
Inibidores Enzimáticos
/
Maleimidas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
China