Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 5, Pages 1179-1188Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.12.026
Keywords
GSK-3 beta inhibitors; Maleimides; Kinase activity; Neuroprotective agents
Funding
- Fundamental Research Funds for the Central Universities, China [JKZD2013006]
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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-3 beta inhibitory activities. Most compounds showed high potency to GSK-3 beta inhibition with high selectivity. Among them, compounds 7c, 7f, 7h, 7l and 7m significantly reduced GSK-3 beta substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3 beta. 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-3b inhibitors with potential neuroprotective activity. (C) 2015 Published by Elsevier Ltd.
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