Design, synthesis, and biological evaluation of novel pyrrolidinone small-molecule Formyl peptide receptor 2 agonists

M. Maciuszek*, A. Ortega-Gomez, S.L. Maas, J. Garrido-Mesa, B. Ferraro, M. Perretti, A. Merritt, G.A.F. Nicolaes, O. Soehnlein, T.M. Chapman

*Corresponding author for this work

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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 (3 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. (C) 2021 Published by Elsevier Masson SAS.
Original languageEnglish
Article number113805
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 15 Dec 2021


  • FPR2
  • Pharmacophore
  • Agonists
  • Neutrophils
  • Resolution of inflammation

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