Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists.

Autor:	Wurtz NR; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Shirude PS; Bristol Myers Squibb, Bangalore, Karnataka 560099, India., Cheney DL; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Lupisella JA; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Chattopadhyay AK; Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore, Karnataka 560099, India., Baligar V; Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore, Karnataka 560099, India., Seshadri B; Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore, Karnataka 560099, India., Anjanappa P; Bristol Myers Squibb, Bangalore, Karnataka 560099, India., Viet A; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Valente MN; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Hsu MY; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Abousleiman M; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Sarodaya S; Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore, Karnataka 560099, India., Tagore DM; Bristol Myers Squibb, Bangalore, Karnataka 560099, India., Dudhgaonkar S; Bristol Myers Squibb, Bangalore, Karnataka 560099, India., Putlur S; Biocon Bristol Myers Squibb Research Center (BBRC), Bangalore, Karnataka 560099, India., Dierks EA; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Ostrowski J; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Wexler RR; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Garcia R; Bristol Myers Squibb, Princeton, New Jersey 08543, United States., Kick EK; Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Aug 12; Vol. 15 (9), pp. 1500-1505. Date of Electronic Publication: 2024 Aug 12 (Print Publication: 2024).
DOI:	10.1021/acsmedchemlett.4c00172
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2024 American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu