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

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-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 Kd value of 0.078 μ m against the RIP1 kinase and an EC50 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. [ABSTRACT FROM AUTHOR]