86816-89-9Relevant academic research and scientific papers
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
scheme or table, p. 5044 - 5057 (2010/03/02)
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.
