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Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N‐formyl peptide receptors agonists
Author(s) -
Vergelli Claudia,
Khlebnikov Andrei I.,
Crocetti Letizia,
Guerrini Gabriella,
Cantini Niccolò,
Kirpotina Liliya N.,
Schepetkin Igor A.,
Cilibrizzi Agostino,
Quinn Mark T.,
Rossi Patrizia,
Paoli Paola,
Giovani Maria Paola
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13913
Subject(s) - pyrazole , pyrazolone , receptor , agonist , chemistry , acetamide , peptide , molecular model , combinatorial chemistry , stereochemistry , biochemistry , organic chemistry
N‐formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4‐(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6‐membered compounds, all exhibiting the same 4‐bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five‐membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.