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

Monika Maciuszek; Almudena Ortega-Gomez; Sanne L Maas; Jose Garrido-Mesa; Bartolo Ferraro; Mauro Perretti; Andy Merritt; Gerry A F Nicolaes; Oliver Soehnlein; Timothy M Chapman

doi:10.1016/j.ejmech.2021.113805

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

Eur J Med Chem. 2021 Dec 15:226:113805. doi: 10.1016/j.ejmech.2021.113805. Epub 2021 Sep 2.

Affiliations

¹ 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. Electronic address: maciuszekmonika@gmail.com.
² Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Munich, Germany.
³ The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
⁴ LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK.
⁵ CARIM - School for Cardiovascular Sciences Department of Biochemistry, Maastricht University, Maastricht, Netherlands.
⁶ Institute for Cardiovascular Prevention (IPEK), LMU Munich Hospital, Munich, Germany; Department of Physiology and Pharmacology (FyFa), Karolinska Institute, Stockholm, Sweden; Institute for Experimental Pathology (ExPat), Centre for Molecular Biology of Inflammation, University of Münster, Münster, Germany.

PMID: 34536667
DOI: 10.1016/j.ejmech.2021.113805

Abstract

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.

Keywords: Agonists; FPR2; Neutrophils; Pharmacophore; Resolution of inflammation.

MeSH terms

Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Pyrrolidinones / chemical synthesis
Pyrrolidinones / chemistry
Pyrrolidinones / pharmacology*
Receptors, Formyl Peptide / agonists*
Receptors, Lipoxin / agonists*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
FPR2 protein, human
Pyrrolidinones
Receptors, Formyl Peptide
Receptors, Lipoxin
Small Molecule Libraries