Format

Send to

Choose Destination
Bioorg Med Chem. 2015 Jul 15;23(14):3913-24. doi: 10.1016/j.bmc.2014.12.007. Epub 2014 Dec 13.

Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2.

Author information

1
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy.
2
Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
3
Department of Chemistry, Altai State Techical University, Barnaul, Russia; Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia.
4
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', via Orabona, 4, 70125 Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.

Abstract

N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S)-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds.

KEYWORDS:

Ca(2+) mobilization; Chiral agonist; Formyl peptide receptor; Metabolic stability; Neutrophil; Ureidopropanamide

PMID:
25549897
PMCID:
PMC4466095
DOI:
10.1016/j.bmc.2014.12.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center