坏死性下垂
吡唑
激酶
IC50型
化学
蛋白激酶A
生物化学
药理学
立体化学
生物
体外
程序性细胞死亡
细胞凋亡
作者
Chan Zou,Yu Xiong,Luyi Huang,Chunli Song,Xiaoai Wu,Linli Li,Shengyong Yang
摘要
Receptor interacting protein 1 ( RIP 1) kinase plays an important role in necroptosis, and inhibitors of the RIP 1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP 1 kinase inhibitor, 1‐(2,4‐dichlorobenzyl)‐3‐nitro‐1 H ‐pyrazole ( 1a ). A number of 1‐benzyl‐1 H ‐pyrazole derivatives were synthesized and structure‐activity relationship ( SAR ) analysis led to the discovery of a potent compound, 4b , which showed a K d value of 0.078 μ m against the RIP 1 kinase and an EC 50 value of 0.160 μ m in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l ‐arginine‐induced pancreatitis mouse model.
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