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Synthesis and Evaluation of 3‐(furo[2,3 ‐b ]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK ‐3 β Inhibitors and Anti‐Ischemic Agents
Author(s) -
Ye Qing,
Li Qiu,
Zhou Yubo,
Xu Lei,
Mao Weili,
Gao Yuanxue,
Li Chenhui,
Xu Yuan,
Xu Yazhou,
Liao Hong,
Zhang Luyong,
Gao Jianrong,
Li Jia,
Pang Tao
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12546
Subject(s) - neuroprotection , in vivo , pharmacology , ischemia , chemistry , glutamate receptor , inhibitory postsynaptic potential , in vitro , brain ischemia , biochemistry , medicine , receptor , biology , microbiology and biotechnology
A series of novel 3‐(furo[2,3 ‐b ]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK ‐3 β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK ‐3 β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK ‐3 β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK ‐3 β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK ‐3 β inhibitors with potential neuroprotective activity against brain ischemic stroke.