Bicyclic imidazole-4-one derivatives: a new class of antagonists for the orphan G protein-coupled receptors GPR18 and GPR55

GPR18 and GPR55 are orphan G protein-coupled receptors (GPCRs) that interact with certain cannabinoid (CB) receptor ligands. In the present study bicyclic imidazole-4-one derivatives were discovered as new scaffolds for the development of antagonists for GPR18 and GPR55. Interaction with CB1 and CB2 receptors was also studied to assess selectivity. The presented extensive structure–activity relationship study of 49 derivatives investigated at all four GPCRs revealed structural requirements for the development of potent and selective GPR18 and GPR55 antagonists. (Z)-(2,3-Difluorobenzylidene)-6,7-dihydro-2H-imidazo[2,1b][1,3]thiazin-3(5H)-one (18) was identified as a selective GPR55 antagonist (IC50 3.15 μM). The most potent GPR18 antagonist was (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1b][1,3]-thiazin-3(5H)-one (32, IC50 0.279 μM, >36-fold selective vs. CB1 and GPR55, 14-fold selective vs. CB2) representing the first selective GPR18 antagonist. The new compounds may serve as lead structures and as tools to explore the (patho-)physiological roles of these orphan GPCRs and their potential as drug targets.