Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure.
Animals
Chemotaxis
/ drug effects
Disease Models, Animal
Drug Evaluation, Preclinical
HEK293 Cells
Heart Failure
/ pathology
Humans
Macrophages
/ cytology
Mice
Microsomes, Liver
/ metabolism
Neutrophils
/ cytology
Phagocytosis
/ drug effects
Pyrrolidinones
/ chemistry
Receptors, Formyl Peptide
/ agonists
Receptors, Lipoxin
/ agonists
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
10 09 2020
10 09 2020
Historique:
pubmed:
15
5
2020
medline:
15
12
2020
entrez:
15
5
2020
Statut:
ppublish
Résumé
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist
Identifiants
pubmed: 32407089
doi: 10.1021/acs.jmedchem.9b02101
doi:
Substances chimiques
FPR1 protein, human
0
FPR2 protein, human
0
Pyrrolidinones
0
Receptors, Formyl Peptide
0
Receptors, Lipoxin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM