Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis

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.