Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists
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 <i>in vivo</i> 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.
Authors
- Daniel L. Cheney (ORCID: https://orcid.org/0009-0008-6994-7688)
- Ruth R. Wexler (ORCID: https://orcid.org/0000-0001-5514-5053)
- Pravin S. Shirude (ORCID: https://orcid.org/0000-0001-5950-6768)
- Shailesh Dudhgaonkar (ORCID: https://orcid.org/0000-0003-1694-3460)
- Nicholas R. Wurtz (ORCID: https://orcid.org/0000-0003-2574-9440)
- Amit K. Chattopadhyay (ORCID: https://orcid.org/0000-0001-5499-6008)
- Elizabeth A. Dierks (ORCID: https://orcid.org/0000-0002-3654-4064)
- Sivaprasad Putlur
- Ricardo Garcı́a
- Vishweshwaraiah Baligar
- Andrew Q. Viet
- John A. Lupisella (ORCID: https://orcid.org/0000-0003-1343-6412)
- Prakash Anjanappa
- Mojgan Abousleiman
- Ellen K. Kick (ORCID: https://orcid.org/0000-0003-3498-4194)
- Debarati M. Tagore
- Sanket Sarodaya
- Meriah N. Valente
- Balaji Seshadri
- Mei-Yin Hsu
- Jacek Ostrowski
Institutions
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb (India) (IN)
- Biocon (India) (IN)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00172
- Citations
- 2
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Bristol-Myers Squibb