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, Ki 8.91 nM) and its 3′-trifluoromethyl
analog (54, PSB-24040, Ki 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.