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Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis

文献类型：期刊论文

作者Chen, Lin-Hai2; Zhang, Qing1,3,4; Xiao, Yu-Feng2,5; Fang, You-Chen1,3; Xie, Xin1,3,4; Nan, Fa-Jun2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-03-10
卷号65期号:5页码:3991-4006
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01813
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Nan, Fa-Jun(fjnan@simm.ac.cn)
英文摘要GPR84 is a proinflammatory G protein-coupled receptor associated with several inflammatory and fibrotic diseases. GPR84 antagonists have been evaluated in clinical trials to treat ulcerative colitis, idiopathic pulmonary fibrosis, and nonalcoholic steatohepatitis. However, the variety of potent and selective GPR84 antagonists is still limited. Through high-throughput screening, a novel phosphodiester compound hit 1 was identified as a GPR84 antagonist. The subsequent structural optimization led to the identification of compound 33 with improved potency in the calcium mobilization assay and the ability to inhibit the chemotaxis of neutrophils and macrophages upon GPR84 activation. In a DSS-induced mouse model of ulcerative colitis, compound 33 significantly alleviated colitis symptoms and reduced the disease activity index score at oral doses of 25 mg/kg qd, with an efficacy similar to that of positive control 5-aminosalicylic acid (200 mg/kg, qd, po), suggesting that compound 33 is a promising candidate for further drug development.
WOS关键词FATTY-ACIDS ; RECEPTOR ; EXPRESSION ; AGONISTS ; LIGANDS
资助项目Personalized Medicines. Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020229] ; National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[22077132] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-002] ; Shanghai Science and Technology Development Funds[20ZR1471200] ; Shanghai Science and Technology Development Funds[20S11903200] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017329] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020283]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000772205900019
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/299883]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Nan, Fa-Jun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Lin-Hai,Zhang, Qing,Xiao, Yu-Feng,et al. Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(5):3991-4006.
APA Chen, Lin-Hai,Zhang, Qing,Xiao, Yu-Feng,Fang, You-Chen,Xie, Xin,&Nan, Fa-Jun.(2022).Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis.JOURNAL OF MEDICINAL CHEMISTRY,65(5),3991-4006.
MLA Chen, Lin-Hai,et al."Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis".JOURNAL OF MEDICINAL CHEMISTRY 65.5(2022):3991-4006.

入库方式： OAI收割

来源：上海药物研究所

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