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Design, synthesis, and biological evaluation of novel pyrrolidinone small-molecule Formyl peptide receptor 2 agonists
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.ejmech.2021.113805
Monika Maciuszek 1 , Almudena Ortega-Gomez 2 , Sanne L Maas 2 , Jose Garrido-Mesa 3 , Bartolo Ferraro 2 , Mauro Perretti 3 , Andy Merritt 4 , Gerry A F Nicolaes 5 , Oliver Soehnlein 6 , Timothy M Chapman 4
Affiliation  

A series of Formyl peptide receptor 2 small molecule agonists with a pyrrolidinone scaffold, derived from a combination of pharmacophore modelling and docking studies, were designed and synthesized. The GLASS (GPCR-Ligand Association) database was screened using a pharmacophore model. The most promising novel ligand structures were chosen and then tested in cellular assays (calcium mobilization and β-arrestin assays). Amongst the selected ligands, two pyrrolidinone compounds (7 and 8) turned out to be the most active. Moreover compound 7 was able to reduce the number of adherent neutrophils in a human neutrophil static adhesion assay which indicates its anti-inflammatory and proresolving properties. Further exploration and optimization of new ligands showed that heterocyclic rings, e.g. pyrazole directly connected to the pyrrolidinone scaffold, provide good stability and a boost in the agonistic activity. The compounds of most interest (7 and 30) were tested in an ERK phosphorylation assay, demonstrating selectivity towards FPR2 over FPR1. Compound 7 was examined in an in vivo mouse pharmacokinetic study. Compound 7 may be a valuable in vivo tool and help improve understanding of the role of the FPR2 receptor in the resolution of inflammation process.



中文翻译:

新型吡咯烷酮小分子甲酰肽受体2激动剂的设计、合成和生物学评价

设计和合成了一系列具有吡咯烷酮支架的甲酰肽受体 2 小分子激动剂,这些激动剂源自药效团建模和对接研究的组合。使用药效团模型筛选 GLASS(GPCR-配体协会)数据库。选择最有希望的新型配体结构,然后在细胞测定(钙动员和 β-抑制蛋白测定)中进行测试。在选定的配体中,两种吡咯烷酮化合物(78)被证明是最活跃的。此外化合物7能够减少人中性粒细胞静态粘附试验中粘附的中性粒细胞的数量,这表明其具有抗炎和促消退特性。对新配体的进一步探索和优化表明,杂环,例如直接连接到吡咯烷酮支架的吡唑,提供了良好的稳定性和激动活性的增强。最感兴趣的化合物(730)在 ERK 磷酸化测定中进行了测试,证明对 FPR2 的选择性优于对 FPR1。在体内小鼠药代动力学研究中检查了化合物7 。化合物7在体内可能是有价值的 工具并帮助提高对 FPR2 受体在消炎过程中的作用的理解。

更新日期:2021-09-15
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