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Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors

文献类型：期刊论文

作者Lan, Yaohan3,4; Ji, Yinchun2; Peng, Xia2; Duan, Wenhu1,3,4; Geng, Meiyu1,2,4; Ai, Jing2,4; Zhang, Hefeng3
刊名ARCHIV DER PHARMAZIE
出版日期2024-07-02
页码21
关键词autoimmune disease necroptosis inhibitor pharmacokinetic profile receptor interacting protein kinase 1 (RIPK1) structural optimization
ISSN号0365-6233
DOI10.1002/ardp.202400302
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Hefeng(zhanghefeng1@simm.ac.cn)
英文摘要Necroptosis is a form of regulated necrotic cell death and has been confirmed to play pivotal roles in the pathogenesis of multiple autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. The development of necroptosis inhibitors may offer a promising therapeutic strategy for the treatment of these autoimmune diseases. Herein, starting from the in-house hit compound 1, we systematically performed structural optimization to discover potent necroptosis inhibitors with good pharmacokinetic profiles. The resulting compound 33 was a potent necroptosis inhibitor for both human I2.1 cells (IC50 < 0.2 nM) and murine Hepa1-6 cells (IC50 < 5 nM). Further target identification revealed that compound 33 was an inhibitor of receptor interacting protein kinase 1 (RIPK1) with favorable selectivity. In addition, compound 33 also exhibited favorable pharmacokinetic profiles (T-1/2 = 1.32 h, AUC = 1157 ngh/mL) in Sprague-Dawley rats. Molecular docking and molecular dynamics simulations confirmed that compound 33 could bind to RIPK1 with high affinity. In silico ADMET analysis demonstrated that compound 33 possesses good drug-likeness profiles. Collectively, compound 33 is a promising candidate for antinecroptotic drug discovery.
WOS关键词AUTOIMMUNE-DISEASE ; TNF-ALPHA
资助项目Natural Science Foundation of China for Innovation Research Group[81821005] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0120231001] ; China Postdoctoral Science Foundation[2023T160663] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences ; Shandong Laboratory Program[SIMM0320231002]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:001260896200001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/312113]  
专题中国科学院上海药物研究所
通讯作者Ai, Jing; Zhang, Hefeng
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Canc Res Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Shanghai Inst Mat Med SIMM, Chinese Acad Sci, Small Mol Drug Res Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Lan, Yaohan,Ji, Yinchun,Peng, Xia,et al. Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors[J]. ARCHIV DER PHARMAZIE,2024:21.
APA Lan, Yaohan.,Ji, Yinchun.,Peng, Xia.,Duan, Wenhu.,Geng, Meiyu.,...&Zhang, Hefeng.(2024).Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors.ARCHIV DER PHARMAZIE,21.
MLA Lan, Yaohan,et al."Discovery and optimization of 3-(indolin-5-yloxy)pyridin-2-amine derivatives as potent necroptosis inhibitors".ARCHIV DER PHARMAZIE (2024):21.

入库方式： OAI收割

来源：上海药物研究所

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