Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists
Year: 2024
Type: article
Abstract: 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.
Source: ACS Medicinal Chemistry Letters
Authors: Nicholas R. Wurtz, Pravin S. Shirude, Daniel L Cheney, John A. Lupisella, Amit Kumar Chattopadhyay, Vishweshwaraiah Baligar, Balaji Seshadri, Prakash Anjanappa, Andrew Viet, Meriah N. Valente, Mei-Yin Hsu, Mojgan Abousleiman, Sanket Sarodaya, Debarati M. Tagore, Shailesh Dudhgaonkar, Sivaprasad Putlur, Elizabeth A. Dierks, Jacek Ostrowski, Ruth R. Wexler, Ricardo Garcia, Ellen K. Kick
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Bristol-Myers Squibb
OpenAlex ID: W4401510347