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

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.