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学术论文
Gang Li, Dongmei Wang, Mingna Sun, Guangyan Li, Jinfeng Hu, Yun Zhang, Yuhe Yuan, Haijie Ji, Naihong Chen*, Gang Liu. Discovery and Optimization of Novel 3-Piperazinyl Coumarin Antagonist of Chemokine – like factor 1 with oral Anti-asthma activity in mice. Journal of Medicinal Chemistry, 2010, 53 (4), 1741–1754.
发布时间:2011-11-16作者:刘刚关键字:

Abstract
Chemokine-like factor 1 (CKLF1) is a novel functional cytokine that acts through its 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 (IC(50) = 4.36 x 10(-6) M) that led to the discovery of orally active compound 41 (IC(50) = 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-kappaB signal pathway."




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