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Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Jul 15; Vol. 23 (14), pp. 3913-24. Date of Electronic Publication: 2014 Dec 13. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amides chemical synthesis
Animals
Calcium metabolism
Chemistry Techniques, Synthetic
Drug Stability
HL-60 Cells drug effects
Humans
Mice, Inbred BALB C
Microsomes, Liver drug effects
Neutrophil Activation drug effects
Rats
Receptors, Formyl Peptide chemistry
Receptors, Lipoxin chemistry
Species Specificity
Stereoisomerism
Amides chemistry
Drug Evaluation, Preclinical methods
Receptors, Formyl Peptide agonists
Receptors, Lipoxin agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 23
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25549897
- Full Text :
- https://doi.org/10.1016/j.bmc.2014.12.007