Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein‐coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)‐3‐(4‐bromophenyl)‐1‐(4‐(4‐methoxybenzoyl)piperazin‐1‐yl)prop‐2‐en‐1‐one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca2+ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure‐activity relationship trends, these were supplemented with five in‐house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy‐switch. Change your stripes: Based on screening of a focused library containing 79 compounds with structural resemblance to the known GPR183 antagonist NIBR189 (5), herein we report the discovery of a novel series of small‐molecule GPR183 agonists, thereby providing clues to a molecular efficacy‐switch for this compound class.