Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors

Bioorg Med Chem Lett. 2015 Mar 15;25(6):1338-42. doi: 10.1016/j.bmcl.2015.01.023. Epub 2015 Jan 20.

Abstract

Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).

Keywords: Diazepine; HSP90 inhibitor; Macrocycle; Oaxazepine; Structure based design.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Amides / chemistry*
  • Amides / metabolism
  • Amides / pharmacology
  • Animals
  • Azepines / chemistry
  • Benzamides / chemistry
  • Benzamides / metabolism
  • Benzodiazepines / chemistry*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology
  • Binding Sites
  • Cell Membrane Permeability / drug effects
  • Crystallography, X-Ray
  • Dogs
  • Drug Evaluation, Preclinical
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology
  • Madin Darby Canine Kidney Cells
  • Molecular Docking Simulation
  • Oxazepines / chemistry*
  • Oxazepines / metabolism
  • Oxazepines / pharmacology
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / metabolism

Substances

  • 2-fluoro-6-(tetrahydrofuran-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide
  • Amides
  • Azepines
  • Benzamides
  • HSP90 Heat-Shock Proteins
  • Indoles
  • Oxazepines
  • ortho-Aminobenzoates
  • Benzodiazepines
  • Adenosine Triphosphate