2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists

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• 作者：Claudia Vergelli^a ; Igor A. Schepetkin^b ; Giovanna Ciciani^a ; Agostino Cilibrizzi^c ; Letizia Crocetti^a ; Maria Paola Giovannoni^a ; ^{mariapaola.giovannoni@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Gabriella Guerrini^a ; Antonella Iacovone^a ; Liliya N. Kirpotina^b ; Andrei I. Khlebnikov^d ; ^e ; Richard D. Ye^f ; Mark T. Quinn^b
• 关键词：Formyl peptide receptor (FPR) ; Agonist ; Pyridazin-3(2H)-one ; Neutrophil ; Ca2+ mobilization
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：24
• 期：11
• 页码：2530-2543
• 全文大小：1497 K

文摘

N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists class="boldFont">8a, class="boldFont">13a and class="boldFont">27b, which had EC₅₀ values in nanomolar range. In particular, compound class="boldFont">8a showed a preference for FPR1 (EC₅₀ = 45 nM), while class="boldFont">13a and class="boldFont">27b showed a moderate preference for FPR2 (EC₅₀ = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.