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

The G protein-coupled receptor 17 (GPR17) is an orphan\nreceptor\ninvolved in inflammatory diseases. GPR17 antagonists have been proposed\nfor the treatment of multiple sclerosis due to their potential to\ninduce remyelination. Potent, selective antagonists are required to\nenable target validation. In the present study, we describe the discovery\nof a novel class of GPR17 antagonists based on an anthranilic acid\nscaffold. The compounds’ potencies were evaluated in calcium\nmobilization and radioligand binding assays, and structure–activity\nrelationships were analyzed. Selected antagonists were additionally\nstudied in cAMP and G protein activation assays. The most potent antagonists\nwere 5-methoxy-2-(5-(3′-methoxy-[1,1′-biphenyl]-2-yl)furan-2-carboxamido)benzoic\nacid (<b>52</b>, PSB-22269, K<sub>i</sub> 8.91 nM) and its 3′-trifluoromethyl\nanalog (<b>54</b>, PSB-24040, K<sub>i</sub> 83.2 nM). Receptor–ligand\ndocking studies revealed that the compounds’ binding site is\ncharacterized by positively charged arginine residues and a lipophilic\npocket. These findings yield valuable insights into this poorly characterized\nreceptor providing a basis for future drug development.