Unsymmetrical Phosphodiesters as GPR84 Antagonists with High Blood Exposure for the Treatment of Lung Inflammation
文献类型：期刊论文
| 作者 | Li, Shao-Xian5; Wang, Si-Wei4,5; Chen, Lin-Hai5 ; Zhang, Qing2,3,4,5; Lu, Dan1,5; Chen, Jing5; Fang, You-Chen5; Gu, Min5; Xie, Xin1,3,4,5; Nan, Fa-Jun3,4,5
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-04-27 |
| 卷号 | 66期号:8页码:5820-5838 |
| DOI | 10.1021/acs.jmedchem.3c00053 |
| 文献子类 | Article |
| 英文摘要 | GPR84 is a proinflammatory G protein-coupled receptor that mediates myeloid immune cell functions. Blocking GPR84 with antagonists is a promising approach for treating inflammatory and fibrotic diseases. Previously, a GPR84 antagonist 604c, with a symmetrical phosphodiester structure, has displayed promising efficacy in a mouse model of ulcerative colitis. However, the low blood exposure resulting from physicochemical properties prevented its uses in other inflammatory diseases. In this study, a series of unsymmetrical phosphodiesters with lower lipophilicity were designed and tested. The representative compound 37 exhibited a 100-fold increase in mouse blood exposure compared to 604c while maintaining in vitro activity. In a mouse model of acute lung injury, 37 (30 mg/kg, po) significantly reduced the infiltration of proinflammatory cells and the release of inflammatory cytokines and ameliorated pathological changes equally or more effectively than N-acetylcysteine (100 mg/ kg, po). These findings suggest that 37 is a promising candidate for treating lung inflammation. |
| WOS关键词 | PROTEIN-COUPLED-RECEPTOR ; EXPRESSION ; INJURY ; MODEL |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000970865200001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309642]  |
| 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.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China; 3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Shao-Xian,Wang, Si-Wei,Chen, Lin-Hai,et al. Unsymmetrical Phosphodiesters as GPR84 Antagonists with High Blood Exposure for the Treatment of Lung Inflammation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(8):5820-5838. |
| APA | Li, Shao-Xian.,Wang, Si-Wei.,Chen, Lin-Hai.,Zhang, Qing.,Lu, Dan.,...&Nan, Fa-Jun.(2023).Unsymmetrical Phosphodiesters as GPR84 Antagonists with High Blood Exposure for the Treatment of Lung Inflammation.JOURNAL OF MEDICINAL CHEMISTRY,66(8),5820-5838. |
| MLA | Li, Shao-Xian,et al."Unsymmetrical Phosphodiesters as GPR84 Antagonists with High Blood Exposure for the Treatment of Lung Inflammation".JOURNAL OF MEDICINAL CHEMISTRY 66.8(2023):5820-5838. |
入库方式： OAI收割
来源：上海药物研究所
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