Enhanced pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists of the HDM2-p53 protein-protein interaction through structure-based drug design

Bioorg Med Chem Lett. 2006 Jun 15;16(12):3310-4. doi: 10.1016/j.bmcl.2006.03.055. Epub 2006 Apr 4.

Abstract

Guided by structure-based drug design, modification of the 1,4-benzodiazepin-2,5-dione lead compound 1 resulted in the discovery of 19, a potent and orally bioavailable antagonist of the HDM2-p53 protein-protein interaction (FP IC50 = 0.7 microM, F approximately 100%).

MeSH terms

  • Alkylation
  • Animals
  • Benzodiazepines / chemical synthesis
  • Benzodiazepines / chemistry*
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Pentanoic Acids / chemistry
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Pentanoic Acids
  • Tumor Suppressor Protein p53
  • Benzodiazepines
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Bz-423