Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2)

J Med Chem. 2003 Jan 2;46(1):49-63. doi: 10.1021/jm020241c.


A series of of 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile derivatives that function as irreversible inhibitors of EGFR and HER-2 kinases have been prepared. These inhibitors have, at the 6-position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or mixed anhydrides. We performed competitive reactivity studies showing that attaching a dialkylamino group onto the end of the Michael acceptor results in compounds with greater reactivity due to intramolecular catalysis of the Michael addition. This, along with improved water-solubility results in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. One compound, 5 (EKB-569), which shows excellent oral in vivo activity, was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

MeSH terms

  • Administration, Oral
  • Aminoquinolines
  • Aniline Compounds
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Glutathione / antagonists & inhibitors
  • Humans
  • Mice
  • Models, Molecular
  • Organic Chemicals*
  • Phosphorylation
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Aminoquinolines
  • Aniline Compounds
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Organic Chemicals
  • ErbB Receptors
  • Receptor, ErbB-2
  • Glutathione
  • EKB 569