LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK; The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Munich, Germany.
Eur J Med Chem. 2021 Mar 15;214:113194. doi: 10.1016/j.ejmech.2021.113194. Epub 2021 Jan 16.
The discovery of natural specialized pro-resolving mediators and their corresponding receptors, such as formyl peptide receptor 2 (FPR2), indicated that resolution of inflammation (RoI) is an active process which could be harnessed for innovative approaches to tame pathologies with underlying chronic inflammation. In this work, homology modelling, molecular docking and pharmacophore studies were deployed to assist the rationalization of the structure-activity relationships of known FPR2 agonists. The developed pharmacophore hypothesis was then used in parallel with the homology model for the design of novel ligand structures and in virtual screening. In the first round of optimization compound 8, with a cyclopentane core, was chosen as the most promising agonist (β-arrestin recruitment EC = 20 nM and calcium mobilization EC = 740 nM). In a human neutrophil static adhesion assay, compound 8 decreased the number of adherent neutrophils in a concentration dependent manner. Further investigation led to the more rigid cycloleucines (compound 22 and 24) with improved ADME profiles and maintaining FPR2 activity. Overall, we identified novel cyclopentane urea FPR2 agonists with promising ADMET profiles and the ability to suppress the inflammatory process by inhibiting the neutrophil adhesion cascade, which indicates their anti-inflammatory and pro-resolving properties.
天然专一性促分解介质及其相应受体（如甲酰肽受体 2（FPR2））的发现表明，炎症消退（RoI）是一个主动的过程，可以利用这一过程来创新地治疗潜在慢性炎症的病理。在这项工作中，采用同源建模、分子对接和药效团研究来协助合理化已知 FPR2 激动剂的构效关系。然后，将开发的药效团假说与同源模型一起用于设计新型配体结构和虚拟筛选。在第一轮优化中，选择具有环戊烷核心的化合物 8 作为最有前途的激动剂（β-抑制蛋白募集 EC = 20 nM 和钙动员 EC = 740 nM）。在人中性粒细胞静态黏附测定中，化合物 8 以浓度依赖的方式减少黏附的中性粒细胞数量。进一步的研究导致了更刚性的环亮氨酸（化合物 22 和 24），具有改善的 ADME 特征并保持 FPR2 活性。总的来说，我们确定了具有有前途的 ADMET 特征的新型环戊烷脲 FPR2 激动剂，能够通过抑制中性粒细胞黏附级联来抑制炎症过程，这表明它们具有抗炎和促分解特性。
