Discovery and Optimization of Novel 3-Piperazinylcoumarin Antagonist of Chemokine-like Factor 1 with Oral Antiasthma Activity in Mice

摘要: Chemokine-like factor 1 (CKLF1) is a novel functional cytokine that acts through its receptor CC chemokine 4 (CCR4). Activation of CCR4 by CKLF1 plays an important role in diseases such as asthma and multiple sclerosis. This article describes cell-based screening assay using FITC-labeled agonist (CKLF1-C27), peptide fragment. Screening our in-stock small-molecule library identified 3-piperazinylcoumarin analogue (IC50 = 4.36 × 10−6 M) led to the discovery orally active compound 41 2.12 10−8 systematic optimization. Compound blocked calcium mobilization chemotaxis induced CKLF1-C27 reduced asthmatic pathologic changes lung tissue human CKLF1-transfected mice. Further studies indicated ameliorated pathological via inhibition NF-κB signal pathway.