期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 8, 页码 5820-5838出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00053
关键词
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GPR84 is a proinflammatory G protein-coupled receptor that plays a role in myeloid immune cell functions. A series of unsymmetrical phosphodiesters were designed and tested as GPR84 antagonists. The representative compound 37 showed increased blood exposure and efficacy in reducing lung inflammation in a mouse model.
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.
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