Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury  

作　　者：Lijuan Xu Ye Tu Jiao Li Wannian Zhang Zhibin Wang Chunlin Zhuang Lei Xue 

机构地区：[1]School of Pharmacy,Second Military Medical University,Shanghai 200433,China [2]Department of Medicine,Shanghai East Hospital,Tongji University,Shanghai 200120,China [3]Shanghai Tenth People’s Hospital,Tongji University School of Medicine,Shanghai 200072,China [4]Shanghai Changzheng Hospital,Second Military Medical University,Shanghai 200433,China [5]Department of Chemistry,Fudan University,Shanghai 200433,China

出　　处：《Chinese Chemical Letters》2022年第5期2545-2549,共5页中国化学快报（英文版）

基　　金：from the National Natural Science Foundation of China(Nos.82022065,81872791,82073696,81872880 and U20A20136);the Key Research and Development Program of Ningxia(No.2019BFG02017,China);the Scientific and Technological Innovation Project of Science and Technology Commission of Shanghai Municipality(No.21S11900800,China).

摘　　要：Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury(ALI).SZM594,a benzothiazole compound previously developed by our research group,possessed good dual-targeting receptor-interacting protein kinase 1(RIPK1)and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy.In this study,the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy.The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594.More importantly,compound 41 could inhibit the tumor necrosis factor-α(TNF-α)ex-pression in lipopolysaccharide(LPS)-induced peritoneal macrophage cell model,and significantly allevi-ate LPS-induced ALI in a mouse model.This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein(MLKL).Thus,these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI.

关 键 词：Acute lung injury RIPK1 RIPK3 NECROPTOSIS Design 

分 类 号：R965[医药卫生—药理学]