Discovery and optimization of novel 3-piperazinylcoumarin antagonist of chemokine-like factor 1 with oral antiasthma activity in mice

Journal of Medicinal Chemistry
Gang LiGang Liu

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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Citations

Jul 10, 2013·European Journal of Medicinal Chemistry·Mingna SunGang Liu
May 10, 2011·European Journal of Pharmacology·Zhi-Peng LiNai-Hong Chen
Nov 15, 2013·Respirology : Official Journal of the Asian Pacific Society of Respirology·Zhi-Hua ChenHua-Hao Shen
Oct 21, 2014·Expert Opinion on Therapeutic Patents·Anna-Maria Katsori, Dimitra Hadjipavlou-Litina
Mar 1, 2014·International Immunopharmacology·Zhipeng LiNaihong Chen
Jul 16, 2013·International Immunopharmacology·Zhipeng LiNaihong Chen
Feb 19, 2017·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Ziqian ZhangYan Li
Aug 22, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hongwei GongSong Li
Jul 28, 2020·Experimental Biology and Medicine·Xiaopeng CaiZhi Chen

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