Synthesis and evaluation of heteroaryl-ketone derivatives as a novel class of VEGFR-2 inhibitors

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4344-7. doi: 10.1016/j.bmcl.2008.06.083. Epub 2008 Jun 28.

Abstract

We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.

MeSH terms

  • Administration, Oral
  • Animals
  • Combinatorial Chemistry Techniques
  • Inhibitory Concentration 50
  • Ketones* / chemical synthesis
  • Ketones* / chemistry
  • Ketones* / pharmacology
  • Mice
  • Molecular Structure
  • Piperidines / pharmacology
  • Quinazolines / pharmacology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • Ketones
  • Piperidines
  • Quinazolines
  • Vascular Endothelial Growth Factor Receptor-2
  • vandetanib