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

Qing Ye; Weili Mao; Yubo Zhou; Lei Xu; Qiu Li; Yuanxue Gao; Jing Wang; Chenhui Li; Yazhou Xu; Yuan Xu; Hong Liao; Luyong Zhang; Jianrong Gao; Jia Li; Tao Pang

doi:10.1016/j.bmc.2014.12.026

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

Bioorg Med Chem. 2015 Mar 1;23(5):1179-88. doi: 10.1016/j.bmc.2014.12.026. Epub 2014 Dec 20.

Authors

Qing Ye¹, Weili Mao², Yubo Zhou³, Lei Xu³, Qiu Li², Yuanxue Gao⁴, Jing Wang⁴, Chenhui Li⁴, Yazhou Xu⁴, Yuan Xu⁴, Hong Liao⁴, Luyong Zhang⁴, Jianrong Gao⁵, Jia Li⁶, Tao Pang⁷

Affiliations

¹ State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
⁵ State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China. Electronic address: gdgjr@zjut.edu.cn.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
⁷ Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tpang@cpu.edu.cn.

PMID: 25662701
DOI: 10.1016/j.bmc.2014.12.026

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.

Keywords: GSK-3β inhibitors; Kinase activity; Maleimides; Neuroprotective agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Glycogen Synthase Kinase 3 beta
Male
Maleimides / chemical synthesis*
Maleimides / chemistry
Maleimides / pharmacology*
Models, Molecular
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Maleimides
Neuroprotective Agents
Glycogen Synthase Kinase 3 beta
Gsk3b protein, rat
Glycogen Synthase Kinase 3