Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases

Bioorg Med Chem Lett. 2012 Jan 1;22(1):456-60. doi: 10.1016/j.bmcl.2011.10.103. Epub 2011 Nov 6.

Abstract

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.

MeSH terms

  • Administration, Oral
  • Animals
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Drug Screening Assays, Antitumor / methods
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / metabolism
  • Models, Chemical
  • Neoplasm Transplantation
  • Pyrimidines / chemistry
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / chemistry
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrimidines
  • ErbB Receptors
  • Receptor, ErbB-2