Discovery and Optimization of Novel 3-Piperazinylcoumarin Antagonist of Chemokine-like Factor 1 with Oral Antiasthma Activity in Mice
Discovery and Optimization of Novel 3-Piperazinylcoumarin Antagonist of Chemokine-like Factor 1 with Oral Antiasthma Activity in Mice
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DOI：
10.1021/jm901652p
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发表时间：
2010-02-25
影响因子：
7.3
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Li, Gang;Wang, Dongmei;Liu, Gang
趋化素样因子1(CKLF1)是一种通过CC趋化因子受体4(CCR4)发挥作用的新型功能性细胞因子。CKLF1激活CCR4在哮喘、多发性硬化等疾病中起重要作用。本文描述了一种使用FITC标记的CCR4激动剂(CKLF1-C27)的细胞筛选方法，CKLF1是一段CKLF1肽片段。对我们现有的小分子文库进行筛选，得到3-哌嗪基香豆素类似物1(IC_(50)=4.36×10~(-6)M)，通过系统优化得到具有口服活性的化合物41(IC_(50)=2.12×10~(-8)M)。化合物41阻断CKLF1-C27诱导的肺组织钙动员和趋化作用，减轻CKLF1转基因小鼠肺组织的哮喘病理改变。进一步的研究表明，化合物41通过抑制核因子-kappaB信号通路来改善病理变化。
Chemokine-like factor 1 (CKLF1) is a novel functional cytokine that acts through receptor CC chemokine receptor 4 (CCR4). Activation of CCR4 by CKLF1 plays an important role in diseases such as asthma and multiple Sclerosis. This article describes a cell-based screening assay Using an FITC-labeled CCR4 agonist (CKLF1-C27), a CKLF1 peptide fragment. Screening of our in-stock small-molecule library identified a 3-piperazinylcoumarin analogue 1 (IC50 = 4.36 x 10(-6) M) that led to the discovery of orally active compound 41 (IC50 = 2.12 x 10(-8) M) through systematic optimization. Compound 41 blocked the calcium mobilization and chemotaxis induced by CKLF1-C27 and reduced the asthmatic pathologic changes in lung tissue of human CKLF1-transfected mice. Further studies indicated that compound 41 ameliorated pathological changes via inhibition of the NF-kappa B signal pathway.