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Chem Biol Drug Des. 2016 Apr;87(4):569-74. doi: 10.1111/cbdd.12689. Epub 2015 Dec 19.

Design, Synthesis, and Biological Evaluation of 1-Benzyl-1H-pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors.

Zou C1,2, Xiong Y1,2, Huang LY1,2, Song CL3, Wu XA1,2, Li LL3, Yang SY1,2.

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State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.


Receptor interacting protein 1 (RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 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 RIP1 kinase inhibitor, 1-(2,4-dichlorobenzyl)-3-nitro-1H-pyrazole (1a). A number of 1-benzyl-1H-pyrazole derivatives were synthesized and structure-activity relationship (SAR) analysis led to the discovery of a potent compound, 4b, which showed a Kd value of 0.078 μm against the RIP1 kinase and an EC50 value of 0.160 μm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l-arginine-induced pancreatitis mouse model.


1-benzyl-1H-pyrazoles; kinase; necroptosis; pancreatitis; receptor interacting protein 1

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