Design, synthesis, and biological evaluation of novel pyrrolidinone small-molecule Formyl peptide receptor 2 agonists
| Autor: | Andy Merritt, Jose Garrido-Mesa, Monika Maciuszek, Timothy M. Chapman, Sanne L. Maas, Oliver Soehnlein, Almudena Ortega-Gomez, Mauro Perretti, Gerry A. F. Nicolaes, Bartolo Ferraro |
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| Přispěvatelé: | Biochemie, RS: Carim - B01 Blood proteins & engineering |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
FPR2
Neutrophils DATABASE Pyrazole Formyl peptide receptor 2 Small Molecule Libraries Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine INFLAMMATION In vivo Drug Discovery Humans SYSTEMIC DELIVERY Receptors Lipoxin Receptor 030304 developmental biology Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure Pharmacophore Ligand A(4) STABLE ANALOGS Anti-Inflammatory Agents Non-Steroidal Organic Chemistry General Medicine Receptors Formyl Peptide Small molecule Combinatorial chemistry Pyrrolidinones Resolution of inflammation 3. Good health MODEL chemistry RESOLUTION Docking (molecular) Drug Design 030217 neurology & neurosurgery Agonists |
| Zdroj: | European Journal of Medicinal Chemistry, 226:113805. Elsevier France-Éditions Scientifiques et Medicales Elsevier |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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