Discovery and structure-activity relationship analyses of 1,2-diphenylethane derivatives as a new class of GPR68 antagonists and the therapeutic effect in an inflammatory bowel disease model

G protein-coupled receptor 68 (GPR68), a proton-sensing GPCR, has emerged as a key player in inflammatory diseases. Its expression is substantially upregulated in the inflamed intestinal mucosa of inflammatory bowel disease (IBD) patients, and pharmacological inhibition of GPR68 has been shown to ameliorate colitis in preclinical models, highlighting GPR68 as a promising therapeutic target. Herein, we report the discovery of diphenylethane derivatives as a novel class of potent GPR68 antagonists. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent GPR68 antagonist (18l) with an IC₅₀ value of 0.081 ± 0.006 μM. The lead compound demonstrated significant inhibition of GPR68-mediated signaling and reduced the production of key pro-inflammatory cytokines. In a dextran sulfate sodium (DSS)-induced mouse model of IBD, 18l effectively alleviated disease symptoms. It also showed good pharmacokinetic properties and a commendable safety profile. Overall, compound 18l could be a promising lead compound for the treatment of IBD and deserves further in-depth studies.

Antagonist; Anti-inflammatory activity; GPR68; Inflammatory bowel disease; Structure–activity relationship.