A quantitative structure-activity relationship study of novel, potent, orally active, selective VEGFR-2 and PDGFRalpha tyrosine kinase inhibitors: derivatives of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea as antitumor agents

J Enzyme Inhib Med Chem. 2008 Apr;23(2):168-73. doi: 10.1080/14756360701450301.

Abstract

The tyrosine kinase inhibitory action of the derivatives of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}urea is quantitatively analyzed using multiple regression analysis. The analysis has helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds for two receptors, namely vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor alpha (PDGFRalpha). From a derived significant correlation equation for inhibition of VEGFR-2, it was concluded that a less hydrophobic molecule with ortho-substituent(s), exerting less steric hindrance and para-substituent devoid of hydrogen-bond acceptor property augment the inhibition action. Besides, a 3-substituent transmitting a higher negative field effect is advantageous to improve the pIC(50) value of a compound. The correlation equation, derived for the inhibition of PDGFRalpha, has revealed that a less hydrophobic molecule, having a 3-substituent which transmits a more negative resonance effect, is helpful in raising its activity. Likewise, in the middle phenyl ring, absence of a fluoro substituent augments the inhibitory activity. Based on derived QSAR equations pertaining to VEGF-2 and PDGFalpha receptors, the drawn guidelines for selection of substituents, may be used to synthesize potent compounds in future.

MeSH terms

  • Administration, Oral
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Molecular Structure
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / chemistry*
  • Phenylurea Compounds / pharmacology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Quantitative Structure-Activity Relationship*
  • Quinolines / chemistry*
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antineoplastic Agents
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Quinolines
  • quinoline
  • Receptor, Platelet-Derived Growth Factor alpha
  • Vascular Endothelial Growth Factor Receptor-2