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Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain

文献类型：期刊论文

作者Chen, Xuetao1,3; Cao, Danyan4; Liu, Chihong1,3; Meng, Fanying1,3; Zhang, Zijian1,3; Xu, Rujun1,3; Tong, Yuanyuan1,3; Xin, Yabing1,3; Zhang, Weikun1,3; Kang, Wenjing1,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-06-29
卷号66期号:13页码:8725-8744
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00372
通讯作者Xiong, Bing(bxiong@simm.ac.cn) ; You, Qidong(youqd@163.com) ; Jiang, Zhengyu(jiangzhengyucpu@163.com)
英文摘要Neuropathic pain (NP) is an intolerable pain syndromethat arisesfrom continuous inflammation and excitability after nerve injury.Only a few NP therapeutics are currently available, and all of themdo not provide adequate pain relief. Herein, we report the discoveryof a selective and potent inhibitor of the bromodomain and extra-terminal(BET) proteins for reducing neuroinflammation and excitability totreat NP. Starting with the screening hit 1 from an in-housecompound library, iterative optimization resulted in the potent BETinhibitor DDO-8926 with a unique binding mode and a novelchemical structure. DDO-8926 exhibits excellent BET selectivityand favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivityby inhibiting pro-inflammatory cytokine expression and reducing excitability.Collectively, these results implicate that DDO-8926 isa promising agent for the treatment of NP.
WOS关键词TARGETING BROMODOMAIN ; EPIGENETIC MECHANISMS ; DRUG DISCOVERY ; FAMILY ; PREGABALIN ; PROTEINS ; DESIGN ; INJURY ; BRD4
资助项目National Natural Science Foundation of China[81930100] ; National Natural Science Foundation of China[82173680] ; Jiangsu Province Funds for Distinguished Young Scientists[BK20220087] ; Young Elite Scientists Sponsorship Program by CAST (China)[YESS20180146] ; Jiangsu Funding Program for Excellent Postdoctoral Talent[2023ZB486] ; Fundamental Research Funds for the Central Universities[2632023GR14]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001018983600001
源URL[http://119.78.100.183/handle/2S10ELR8/306340]  
专题中国科学院上海药物研究所
通讯作者Xiong, Bing; You, Qidong; Jiang, Zhengyu
作者单位1.China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 210009, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.China Pharmaceut Univ, Jiang Su Key Lab Drug Design & Optimizat, State Key Lab Nat Med, Nanjing 210009, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Xuetao,Cao, Danyan,Liu, Chihong,et al. Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(13):8725-8744.
APA Chen, Xuetao.,Cao, Danyan.,Liu, Chihong.,Meng, Fanying.,Zhang, Zijian.,...&Jiang, Zhengyu.(2023).Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain.JOURNAL OF MEDICINAL CHEMISTRY,66(13),8725-8744.
MLA Chen, Xuetao,et al."Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain".JOURNAL OF MEDICINAL CHEMISTRY 66.13(2023):8725-8744.

入库方式： OAI收割

来源：上海药物研究所

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