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.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Zou C,Xiong Y,Huang LY,Song CL,Wu XA,Li LL,Yang SYdoi
10.1111/cbdd.12689subject
Has Abstractpub_date
2016-04-01 00:00:00pages
569-74issue
4eissn
1747-0277issn
1747-0285journal_volume
87pub_type
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