6-Methyl-2,4-Disubstituted Pyridazin-3(2H)-ones: A Novel Class of Small-Molecule Agonists for Formyl Peptide Receptors

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• 作者：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 Verge
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5044-5057
• 全文大小：1028K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

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 (EC₅₀ = 0.6 μM) was the mixed FPR/FPRL1 agonist 14h.