Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors

Bioorg Med Chem Lett. 2008 Apr 15;18(8):2691-5. doi: 10.1016/j.bmcl.2008.03.021. Epub 2008 Mar 10.

Abstract

We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).

MeSH terms

  • 3T3 Cells
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Drug Design*
  • Hydrogen Bonding
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Azepines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptor Protein-Tyrosine Kinases
  • pyrimidine