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Synthesis of Five‐ and Six‐Membered N ‐Phenylacetamido Substituted Heterocycles as Formyl Peptide Receptor Agonists
Author(s) -
Vergelli Claudia,
Schepetkin Igor A.,
Ciciani Giovanna,
Cilibrizzi Agostino,
Crocetti Letizia,
Giovani Maria Paola,
Guerrini Gabriella,
Iacovone Antonella,
Kirpotina Liliya N.,
Ye Richard D.,
Quinn Mark T.
Publication year - 2017
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21370
Subject(s) - gene isoform , agonist , receptor , chemistry , g protein coupled receptor , formyl peptide receptor , peptide , pharmacology , biochemistry , biology , chemotaxis , gene
Preclinical ResearchFormyl peptide receptors (FPRs) are G‐protein‐coupled receptors that play an important role in the regulation of inflammatory process and cellular dysfunction. In humans, three different isoforms are expressed (FPR1, FPR2, and FPR3). FPR2 appears to be directly involved in the resolution of inflammation, an active process carried out by specific pro‐resolving mediators that modulate specific receptors. Previously, we identified 2‐arylacetamido pyridazin‐3(2 H )‐ones as FPR1‐ or FPR2‐selective agonists, as well as a large number of mixed‐agonists for the three isoforms. Here, we report a new series of 2‐arylacetamido pyridazinones substituted at position 5 and their development as FPR agonists. We also synthesized a new series of 2‐oxothiazolones bearing a 4‐bromophenylacetamido fragment, which was fundamental for activity in the pyridazinone series. The compounds of most interest were 4a , a potent, mixed FPR agonist recognized by all three isotypes (FPR1 EC 50 = 19 nM, FPR2 EC 50 = 43 nM, FPR3 EC 50 = 40 nM), and 4b , which had potent activity and a preference for FPR2 (EC 50 = 13 nM). These novel compounds may represent valuable tools for studying FPR activation and signaling. Drug Dev Res 78 : 49–62, 2017. © 2016 Wiley Periodicals, Inc.