Abstract by Loukas Ieremias

GPR84 is a pro-inflammatory receptor and upon its activation on leukocytes enhances the release of inflammatory cytokines. The receptor is upregulated in conditions where inflammation is involved, such as acute respiratory distress syndrome, inflammatory bowel disease, esophagitis, neuropathic pain and fibrosis. In contrast, activation of the receptor may exert a protective role in other diseases such as schizophrenia, Alzheimer’s, osteoporosis, osteoarthritis, obesity, and atherosclerosis. Due to these double-sided properties of GPR84, compounds that either activate or block the receptor’s activity are both of therapeutic interest. In the absence of a crystal structure, High-throughput screening has been used and already resulted in the identification of compounds that can modulate the receptor. Compounds able to promote interaction of GPR84 selectively with the G-protein over the β-arrestin have also been described in the literature and the finding that biased signaling induces very little or no leukocyte chemotaxis opens additional therapeutic possibilities.

Aiming at further exploring the binding pocket of GPR84, a structure-activity relationship (SAR) study was initiated starting from cmpd51, one of the most potent GPR84 agonists in the literature. After iterative cycles of synthesis and in vitro potency evaluation of numerous compounds, we determined positions on the scaffold where heteroatoms were tolerated, making the compounds less lipophilic and therefore potentially better drug candidates. Taking advantage of different in vitro functional assays, compounds expressing biased agonism on the receptor were also identified. Finally, the tautomeric form and the pKa of this class of compounds were investigated for the first time, contributing to the understanding of key interactions within the binding pocket.

Further exploitation of the cmpd51 led to the discovery of a novel GPR84 antagonist. The structural switch that converts a GPR84 agonist into an antagonist was identified and a Schild plot analysis suggests that the novel compounds compete with agonists for the orthosteric binding pocket. A SAR investigation followed, which led to the development of antagonists that are approximately 30-times more potent than the starting point, comprising simultaneously lower lipophilicity. Since GPR84 antagonists will be used in the future in mouse disease models, the activity of selected compounds was also assessed in the mouse receptor orthologue.

Overall, this study provides a spectrum of novel compounds modulating the GPR84. Selected compounds of both the agonist and antagonist series, as well as biased compounds with improved physicochemical properties can potentially enable studies in the future both in vitro and in vivo to further understand the receptor’s pharmacology. After evaluation of their pharmacokinetic properties, compounds of the antagonist series may ultimately serve as leads for the development of new drug candidates.