2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists
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Accepted version
Author(s)
Type
Journal Article
Abstract
N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
Date Issued
2016-04-08
Date Acceptance
2016-04-08
Citation
Bioorganic & Medicinal Chemistry, 2016, 24 (11), pp.2530-2530
ISSN
1464-3391
Publisher
Elsevier
Start Page
2530
End Page
2530
Journal / Book Title
Bioorganic & Medicinal Chemistry
Volume
24
Issue
11
Copyright Statement
© 2016 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Identifier
PII: S0968-0896(16)30253-X
Subjects
Agonist
Ca(2+) mobilization
Formyl peptide receptor (FPR)
Neutrophil
Pyridazin-3(2H)-one
Medicinal & Biomolecular Chemistry
0304 Medicinal And Biomolecular Chemistry
1115 Pharmacology And Pharmaceutical Sciences
0305 Organic Chemistry
Publication Status
Published