Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists.
Nicholas R WurtzPravin S ShirudeDaniel L CheneyJohn A LupisellaAmit Kumar ChattopadhyayVishweshwaraiah BaligarBalaji SeshadriPrakash AnjanappaAndrew VietMeriah N ValenteMei-Yin HsuMojgan AbousleimanSanket SarodayaDebarati M TagoreShailesh DudhgaonkarSivaprasad PutlurElizabeth A DierksJacek OstrowskiRuth R WexlerRicardo GarciaEllen K KickPublished in: ACS medicinal chemistry letters (2024)
We report the discovery and optimization of aryl piperidinone urea formyl peptide receptor 2 (FPR2) agonists from a weakly active high-throughput screening (HTS) hit to potent and selective agonists with favorable efficacy in acute in vivo models. A basis for the selectivity for FPR2 over FPR1 is proposed based on docking molecules into recently reported FPR2 and FPR1 cryoEM structures. Compounds from the new scaffold reported in this study exhibited superior potency and selectivity and favorable ADME profiles. Furthermore, select compounds were evaluated in an acute rat lipopolysaccharide (LPS) inflammation model and demonstrated robust dose-dependent induction of IL10, a marker for inflammation resolution, providing a valuable proof of concept for this class of FPR2 agonists.