6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones: A novel class of small-molecule agonists for formyl peptide receptors

Agostino Cilibrizzi, Mark T. Quinn, Liliya N. Kirpotina, Igor A. Schepetkin, Jeff Holderness, Richard D. Ye, Marie Josephe Rabiet, Claudio Biancalani, Nicoletta Cesari, Alessia Graziano, Claudia Vergelli, Stefano Pieretti, Vittorio Dal Piaz, Maria Paola Giovannoni

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Following a ligand-based drug design approach, a potent mixed formyl peptide receptor 1 (FPR1) and formyl peptide receptor-like 1 (FPRL1) agonist (14a) and a potent and specific FPRL1 agonist (14x) were identified. These compounds belong to a large series of pyridazin-3(2H)-one derivatives substituted with a methyl group at position 6 and a methoxy benzyl at position 4. At position 2, an acetamide side chain is essential for activity. Likewise, the presence of lipophilic and/or electronegative substituents in the position para to the aryl group at the end of the chain plays a critical role for activity. Affinity forFPR1 receptors was evaluated by measuring intracellular calcium flux in HL-60 cells transfected with FPR1, FPRL1, and FPRL2. Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Themost potent chemotactic agent (EC50 =0.6 μM) was the mixed FPR/FPRL1 agonist 14h.

Original languageEnglish
Pages (from-to)5044-5057
Number of pages14
JournalJournal of Medicinal Chemistry
Volume52
Issue number16
DOIs
Publication statusPublished - 27 Aug 2009
Externally publishedYes

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Formyl Peptide Receptor
Calcium
HL-60 Cells
Drug Design
Chemotaxis
Neutrophils
Ligands

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones : A novel class of small-molecule agonists for formyl peptide receptors. / Cilibrizzi, Agostino; Quinn, Mark T.; Kirpotina, Liliya N.; Schepetkin, Igor A.; Holderness, Jeff; Ye, Richard D.; Rabiet, Marie Josephe; Biancalani, Claudio; Cesari, Nicoletta; Graziano, Alessia; Vergelli, Claudia; Pieretti, Stefano; Dal Piaz, Vittorio; Giovannoni, Maria Paola.

In: Journal of Medicinal Chemistry, Vol. 52, No. 16, 27.08.2009, p. 5044-5057.

Research output: Contribution to journalArticle

Cilibrizzi, A, Quinn, MT, Kirpotina, LN, Schepetkin, IA, Holderness, J, Ye, RD, Rabiet, MJ, Biancalani, C, Cesari, N, Graziano, A, Vergelli, C, Pieretti, S, Dal Piaz, V & Giovannoni, MP 2009, '6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones: A novel class of small-molecule agonists for formyl peptide receptors', Journal of Medicinal Chemistry, vol. 52, no. 16, pp. 5044-5057. https://doi.org/10.1021/jm900592h
Cilibrizzi, Agostino ; Quinn, Mark T. ; Kirpotina, Liliya N. ; Schepetkin, Igor A. ; Holderness, Jeff ; Ye, Richard D. ; Rabiet, Marie Josephe ; Biancalani, Claudio ; Cesari, Nicoletta ; Graziano, Alessia ; Vergelli, Claudia ; Pieretti, Stefano ; Dal Piaz, Vittorio ; Giovannoni, Maria Paola. / 6-Methyl-2,4-disubstituted pyridazin-3(2H)-ones : A novel class of small-molecule agonists for formyl peptide receptors. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 16. pp. 5044-5057.
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