Further studies on 2-arylacetamide pyridazin-3(2H)-ones: Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists

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• 作者：Maria Paola Giovannoni^a ; ^{mariapaola.giovannoni@unifi.it} ; Igor A. Schepetkin^b ; Agostino Cilibrizzi^a ; Letizia Crocetti^a ; Andrei I. Khlebnikov^c ; Claes Dahlgren^d ; Alessia Graziano^a ; Vittorio Dal Piaz^a ; Liliya N. Kirpotina^b ; Serena Zerbinati^a ; Claudia Vergelli^a ; Mark T. Quinn^b
• 关键词：Pyridazin-3(2H)-one ; Formyl peptide receptor ; Dual agonist ; Human neutrophils ; Molecular docking
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：64
• 期：Complete
• 页码：512-528
• 全文大小：1438 K

文摘

Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca²⁺ flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC₅₀ values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca²⁺ flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists.