Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan.
Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States.
J Med Chem. 2020 Sep 10;63(17):9003-9019. doi: 10.1021/acs.jmedchem.9b02101. Epub 2020 May 24.
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist , BMS-986235/LAR-1219. In cellular assays inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.
甲酰肽受体 2（FPR2）激动剂可刺激炎症消退，对于治疗由慢性炎症引起的疾病可能具有一定的作用，包括心力衰竭。我们报告了一种强效且选择性的 FPR2 激动剂的发现及其在心力衰竭小鼠模型中的评估。具有中等激动活性的简单线性脲作为优化的起点。引入吡咯烷酮核心可以获得刚性构象，从而产生强效的 FPR2 和 FPR1 激动剂。对内酯取代基的优化导致发现了 FPR2 选择性激动剂 BMS-986235/LAR-1219。在细胞测定中，抑制中性粒细胞趋化作用并刺激巨噬细胞吞噬作用，这些是促进炎症消退的关键终点。在接受 BMS-986235/LAR-1219 治疗后，在心力衰竭小鼠模型中观察到心脏结构和功能的改善。
