Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors

J Med Chem. 2005 Sep 22;48(19):6066-83. doi: 10.1021/jm050458h.

Abstract

A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Edema / chemically induced
  • Edema / pathology
  • Estradiol
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Models, Molecular
  • NIH 3T3 Cells
  • Phosphorylation
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis*
  • Urea / chemistry
  • Urea / pharmacology
  • Uterus / drug effects
  • Uterus / pathology
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyrimidines
  • thienopyrimidine
  • Estradiol
  • Adenosine Triphosphate
  • Urea
  • Receptors, Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor Receptor-2