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

Index: J. Med. Chem. 52 , 5044-57, (2009)

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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 for FPR1 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. The most potent chemotactic agent (EC(50) = 0.6 microM) was the mixed FPR/FPRL1 agonist 14h.