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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-3β inhibitors and neuroprotective agents
- Source :
- Bioorganic & Medicinal Chemistry. 23:1179-1188
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
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-3β inhibitory activities. Most compounds showed high potency to GSK-3β inhibition with high selectivity. Among them, compounds 7c, 7f, 7h, 7l and 7m significantly reduced GSK-3β substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3β. 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-3β inhibitors with potential neuroprotective activity.
- Subjects :
- Male
Models, Molecular
Clinical Biochemistry
Ischemia
Pharmaceutical Science
Pharmacology
Inhibitory postsynaptic potential
Biochemistry
Neuroprotection
Maleimides
Rats, Sprague-Dawley
Glycogen Synthase Kinase 3
Structure-Activity Relationship
In vivo
Drug Discovery
medicine
Animals
Potency
Enzyme Inhibitors
Kinase activity
Molecular Biology
Glycogen Synthase Kinase 3 beta
Chemistry
Organic Chemistry
Glutamate receptor
medicine.disease
In vitro
Rats
Neuroprotective Agents
Molecular Medicine
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....445eb3a7aa695fcfa2bac1a6ab92a535