Wurtz Nicholas R, Shirude Pravin S, Cheney Daniel L, Lupisella John A, Chattopadhyay Amit Kumar, Baligar Vishweshwaraiah, Seshadri Balaji, Anjanappa Prakash, Viet Andrew, Valente Meriah N, Hsu Mei-Yin, Abousleiman Mojgan, Sarodaya Sanket, Tagore Debarati M, Dudhgaonkar Shailesh, Putlur Sivaprasad, Dierks Elizabeth A, Ostrowski Jacek, Wexler Ruth R, Garcia Ricardo, Kick Ellen K
Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
Bristol Myers Squibb, Bangalore, Karnataka 560099, India.
ACS Med Chem Lett. 2024 Aug 12;15(9):1500-1505. doi: 10.1021/acsmedchemlett.4c00172. eCollection 2024 Sep 12.
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 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.
我们报告了从一个活性较弱的高通量筛选（HTS）命中化合物发现并优化芳基哌啶酮尿素甲酰肽受体2（FPR2）激动剂，使其成为在急性模型中具有高效能和选择性且疗效良好的激动剂的过程。基于将分子对接至最近报道的FPR2和FPR1冷冻电镜结构，提出了FPR2相对于FPR1具有选择性的依据。本研究报道的新支架化合物表现出卓越的效能、选择性和良好的药物代谢动力学性质。此外，对选定的化合物在急性大鼠脂多糖（LPS）炎症模型中进行了评估，结果表明其能强力诱导炎症消退标志物IL10，且呈剂量依赖性，为这类FPR2激动剂提供了有价值的概念验证。
