Design, Synthesis, and Characterization of Novel Small Molecule Antagonists of the GPR17 Receptor

Abstract GPR17, an orphan G protein-coupled receptor, negatively regulates oligodendrocyte differentiation and myelination. Inhibiting GPR17 through selective antagonism is a promising strategy to promote endogenous remyelination in disorders like multiple sclerosis. Through rational structural modification of Pranlukast, a nonselective CysLT1 antagonist, we identified novel, selective small molecule GPR17 antagonist leads 39 and 44. These compounds exhibit GPR17 antagonist potencies (IC50) of ∼400−500 nM, with >5000-fold reduced potency at CysLT1 and minimal off-target activity at closely related CysLT2, P2Y1, P2Y2, P2Y4, and P2Y6 receptors. Structure-based modeling using the cryo-EM structure of GPR17 and the crystal structure of CysLT1 provided insights into the observed potency and selectivity. Treatment of isolated rat OPCs with early selective GPR17 antagonist 22 (10 μM) increased MBP expression and Olig2+ cell expansion, underscoring GPR17’s role in promoting OPC differentiation and myelination. Compounds 39 and 44 represent promising leads for further optimization into potent, drug-like GPR17 antagonists.