Discovery of a First-in-Class GPR183 Antagonist for the Potential Treatment of Rheumatoid Arthritis

GPR183
is required for humoral immune responses, and
its polymorphisms
have been associated with inflammatory autoimmune diseases. Despite
increasing attention to GPR183 as a potential therapeutic target for
autoimmune diseases, relatively few antagonists have been reported,
and none of them have progressed to the clinical stage. In this study,
we discovered a highly potent GPR183 antagonist, compound 32, with good aqueous solubility, excellent selectivity, and pharmacokinetic
properties. Meanwhile, compound 32 showed exceptional
efficacy for rheumatoid arthritis (RA) disease in a mouse collagen-induced
arthritis (CIA) model, with an efficacious dose of 0.1 mg/kg. Functionally,
compound 32 significantly reduced the swelling of paws
and joints, the gene expression of proinflammatory cytokines, MCP-1,
MMPs, and VEGF, inflammatory cell infiltration, cartilage damage,
pannus formation, and bone erosion in the joints of CIA mice in a
dose-dependent manner. Hence, these findings suggest compound 32 as a valuable molecule for further development.