Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino 50019 Firenze, Italy.
J Med Chem. 2009 Aug 27;52(16):5044-57. doi: 10.1021/jm900592h.
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.
基于配体的药物设计方法，鉴定出一种有效的混合形式的肽受体 1（FPR1）和形式肽受体样 1（FPRL1）激动剂（14a）和一种有效的和特异性的 FPRL1 激动剂（14x）。这些化合物属于一个大型的嘧啶-3（2H）-一取代的衍生物，在 6 位取代有一个甲基和 4 位取代有一个甲氧苄基。在 2 位，乙酰氨基侧链对于活性是必不可少的。同样，在链末端的芳基的对位取代有亲脂性和/或电负性取代基对于活性也起着关键作用。通过测量转染 FPR1、FPRL1 和 FPRL2 的 HL-60 细胞中的细胞内钙流来评估对 FPR1 受体的亲和力。激动剂能够激活人嗜中性粒细胞中的细胞内钙动员和趋化性。最有效的趋化剂（EC（50）= 0.6 μM）是混合的 FPR/FPRL1 激动剂 14h。
