Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding

Bioorg Med Chem Lett. 2004 Jan 19;14(2):351-5. doi: 10.1016/j.bmcl.2003.11.007.

Abstract

Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.

MeSH terms

  • Animals
  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Dogs
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Ether-A-Go-Go Potassium Channels
  • Humans
  • Microsomes, Liver / enzymology
  • Potassium Channels / metabolism*
  • Potassium Channels, Voltage-Gated*
  • Protein Binding / physiology
  • Quinolones / chemistry
  • Quinolones / pharmacokinetics*
  • Rats
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Cation Transport Proteins
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Quinolones
  • Vascular Endothelial Growth Factor Receptor-2