Discovery of Anthranilic Acid Derivatives as Antagonists of the Pro-Inflammatory Orphan G Protein-Coupled Receptor GPR17

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds’ potencies were evaluated in calcium mobilization and radioligand binding assays, and structure–activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3′-methoxy-[1,1′-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, K_i 8.91 nM) and its 3′-trifluoromethyl analog (54, PSB-24040, K_i 83.2 nM). Receptor–ligand docking studies revealed that the compounds’ binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.