Discovery\nand Optimization of Aryl Piperidinone Ureas\nas Selective Formyl Peptide Receptor 2 Agonists

We report the discovery and optimization of aryl piperidinone\nurea\nformyl peptide receptor 2 (FPR2) agonists from a weakly active high-throughput\nscreening (HTS) hit to potent and selective agonists with favorable\nefficacy in acute <i>in vivo</i> models. A basis for the\nselectivity for FPR2 over FPR1 is proposed based on docking molecules\ninto recently reported FPR2 and FPR1 cryoEM structures. Compounds\nfrom the new scaffold reported in this study exhibited superior potency\nand selectivity and favorable ADME profiles. Furthermore, select compounds\nwere evaluated in an acute rat lipopolysaccharide (LPS) inflammation\nmodel and demonstrated robust dose-dependent induction of IL10, a\nmarker for inflammation resolution, providing a valuable proof of\nconcept for this class of FPR2 agonists.