Unsymmetrical Phosphodiesters as GPR84 Antagonists with High Blood Exposure for the Treatment of Lung Inflammation

Abstract

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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“…The G protein–coupled receptor 84 (GPR84) is a medium-chain fatty acid receptor associated with inflammatory and immune responses. − GPR84 is primarily expressed on the surface of innate immune cells, including neutrophils, monocytes, and macrophages. − Notably, inflammatory stimuli, such as lipopolysaccharide (LPS), tumor necrosis factor α, and interleukin 33 can significantly upregulate GPR84 in these cells. ,, GPR84 activation exacerbates inflammatory cascades in neutrophils and macrophages, while its inhibition attenuates these responses. , GPR84 has long remained understudied, until the recent discovery of chemical agonists and antagonists revealed its value in regulating innate immune and inflammatory responses in various diseases such as inflammatory bowel disease (IBD), , kidney and pulmonary fibrosis, , and acute lung injury (ALI) . Drug candidates targeting GPR84, such as GLPG1205, have previously been evaluated in clinical trials, and many others are being investigated in the preclinical stage, highlighting their therapeutic potential. ,,, …”

“…Structure of representative GPR84 antagonists ,− , and the workflow in this study. (A) Structure of previously reported GPR84 antagonists.…”