title: 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.
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.
authors: 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.
authors: Qing
authors: Q
authors: Ye
authors: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China.
authors: Weili
authors: W
authors: Mao
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Yubo
authors: Y
authors: Zhou
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors: Lei
authors: L
authors: Xu
authors: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China.
authors: Qiu
authors: Q
authors: Li
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Yuanxue
authors: Y
authors: Gao
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Jing
authors: J
authors: Wang
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Chenhui
authors: C
authors: Li
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Yazhou
authors: Y
authors: Xu
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Yuan
authors: Y
authors: Xu
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Hong
authors: H
authors: Liao
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
authors: Luyong
authors: L
authors: Zhang
authors: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, China. Electronic address: gdgjr@zjut.edu.cn.
authors: Jianrong
authors: J
authors: Gao
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
authors: Jia
authors: J
authors: Li
authors: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tpang@cpu.edu.cn.
authors: Tao
authors: T
authors: Pang
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008301:Maleimides; D018696:Neuroprotective Agents; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: GSK-3β inhibitors; Kinase activity; Maleimides; Neuroprotective agents