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

J Med Chem. 2010 Feb 25;53(4):1741-54. doi: 10.1021/jm901652p.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Asthmatic Agents / chemical synthesis*
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Asthma / drug therapy
  • Asthma / immunology
  • Asthma / pathology
  • Binding, Competitive
  • Calcium / metabolism
  • Cell Line
  • Chemokines / antagonists & inhibitors*
  • Chemokines / chemistry
  • Chemokines / genetics
  • Chemotaxis / drug effects
  • Coumarins / chemical synthesis*
  • Coumarins / chemistry
  • Coumarins / pharmacology
  • Fibrosis
  • High-Throughput Screening Assays
  • Humans
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • MARVEL Domain-Containing Proteins
  • Mice
  • NF-kappa B / physiology
  • Peptide Fragments / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Receptors, CCR4 / biosynthesis
  • Receptors, CCR4 / genetics
  • Signal Transduction
  • Structure-Activity Relationship

Substances

  • 5,7-dihydroxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one
  • Anti-Asthmatic Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • CCR4 protein, human
  • CKLF protein, human
  • Chemokines
  • Coumarins
  • MARVEL Domain-Containing Proteins
  • NF-kappa B
  • Peptide Fragments
  • Piperazines
  • Receptors, CCR4
  • Calcium