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Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3′-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury

文献类型：期刊论文

作者Chen, Mingjie4,5; Lei, Shuyue2,3; Zhou, Zihua4,5; Wang, Meng1; Feng, Chunlan2,3; Gao, Xiaoling4,5; Ding, Chunyong4,5; Song, Zilan4,5; Tang, Wei2,3; Zhang, Ao4,5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-04-15
页码24
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02229
通讯作者Song, Zilan(songalan@sjtu.edu.cn) ; Tang, Wei(tangwei@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3 '-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.
WOS关键词GMP-AMP SYNTHASE
资助项目Innovative Research Team of High-level Local University in Shanghai[Technology-2030] ; Innovative Research Team of High-level Local University in Shanghai[2021ZD0204004] ; China National Innovation of Science[82273767] ; China National Innovation of Science[82073073] ; China National Innovation of Science[82122045] ; National Natural Science Foundation of China[ZJ2021-ZD-007] ; Major Projects for Shanghai Zhang Jiang National Independent Innovation of China[SHSMU-ZDCX20210802] ; Innovative research team of high-level local universities in Shanghai
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001203926300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310756]  
专题中国科学院上海药物研究所
通讯作者Song, Zilan; Tang, Wei; Zhang, Ao
作者单位1.Anhui Univ Sci & Technol, Sch Med, Huainan 232001, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Shanghai Jiao Tong Univ, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
5.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Mingjie,Lei, Shuyue,Zhou, Zihua,et al. Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3′-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:24.
APA Chen, Mingjie.,Lei, Shuyue.,Zhou, Zihua.,Wang, Meng.,Feng, Chunlan.,...&Zhang, Ao.(2024).Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3′-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.JOURNAL OF MEDICINAL CHEMISTRY,24.
MLA Chen, Mingjie,et al."Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3′-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury".JOURNAL OF MEDICINAL CHEMISTRY (2024):24.

入库方式： OAI收割

来源：上海药物研究所

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