Potent CCR4 antagonists: synthesis, evaluation, and docking study of 2,4-diaminoquinazolines

Bioorg Med Chem. 2008 Sep 1;16(17):7968-74. doi: 10.1016/j.bmc.2008.07.062. Epub 2008 Jul 29.


A series of CC chemokine receptor-4 (CCR4) antagonists were examined in a previous report in an attempt to improve metabolic stability in human liver microsomes. In this study, the cycloheptylamine moiety of N-cycloheptyl-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 1 was replaced with the p-chloroaniline moiety, and the resulting compound, N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine (8c), retained its potency ([(35)S]GTPgammaS-binding inhibition and CCL22-induced chemotaxis in humans/mice). Based on the structure-activity relationships (SAR), a homology model was constructed for CCR4 to explain the binding mode of 8c. Overall, there was good agreement between the docking pose of the CCR4 homology model and the human [(35)S]GTPgammaS assay results. Administration of 8c in a murine model of acute dermatitis showed anti-inflammatory activity (oxazolone-induced contact hypersensitivity test).

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Computer Simulation*
  • Drug Evaluation, Preclinical
  • Humans
  • Injections, Subcutaneous
  • Mice
  • Models, Chemical*
  • Models, Molecular
  • Molecular Structure
  • Oxazolone
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Receptors, CCR4 / antagonists & inhibitors*
  • Receptors, CCR4 / chemistry
  • Skin Diseases / chemically induced
  • Skin Diseases / drug therapy
  • Skin Diseases / pathology
  • Stereoisomerism
  • Structure-Activity Relationship


  • CCR4 protein, human
  • Ccr4 protein, mouse
  • Quinazolines
  • Receptors, CCR4
  • Oxazolone
  • 2,4-diaminoquinazoline