title: Design, Synthesis, and Biological Evaluation of 1-Benzyl-1H-pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors.
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.
authors.affiliation: 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.
authors.forename: Chan
authors.initials: C
authors.lastname: Zou
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: 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.
authors.forename: Lu-Yi
authors.initials: LY
authors.lastname: Huang
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Xiao-Ai
authors.initials: XA
authors.lastname: Wu
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000818:Animals; D015195:Drug Design; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles
keywords: 1-benzyl-1H-pyrazoles; kinase; necroptosis; pancreatitis; receptor interacting protein 1