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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.

Author information

1
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
2
Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
3
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.

Abstract

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.

KEYWORDS:

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

PMID:
26577270
DOI:
10.1111/cbdd.12689
[Indexed for MEDLINE]

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