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Synthesis and Pharmacological Evaluation of New Pyridazin‐Based Thioderivatives as Formyl Peptide Receptor ( FPR ) Agonists
Author(s) -
Crocetti Letizia,
Vergelli Claudia,
Cilibrizzi Agostino,
Graziano Alessia,
Khlebnikov Andrei I.,
Kirpotina Liliya N.,
Schepetkin Igor A.,
Quinn Mark T.,
Giovani Maria Paola
Publication year - 2013
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.21076
Subject(s) - chemistry , chemotaxis , formyl peptide receptor , agonist , receptor , thio , peptide , pyridazine , biochemistry , stereochemistry , gene isoform , biological activity , intracellular , in vitro , gene
Preclinical ResearchA new series of pyridazinone‐based thioderivatives and pyridazine analogs was synthesized and tested for their ability to bind to the three human formyl peptide receptor ( FPR ) isoforms ( FPR1 , FPR2 , and FPR3 ) and to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Among the pyridazin‐3(2 H )‐one derivatives tested, analogs 8b and 8c were mixed FPR1 / FPR2 agonists, with median effective concentration values in the micromolar range, and were able to activate chemotaxis and Ca 2 + flux in human neutrophils in the low micromolar range. Molecular docking studies showed that interaction of a ligand with Arg205 of FPR1 is important for FPR1 agonist activity. For FPR2 , differences in activity between oxygen‐containing compounds and their thio‐analogs were due to steric bulkiness of sulfur‐containing groups.