Identification of pharmacophore model, synthesis and biological evaluation of N-phenyl-1-arylamide and N-phenylbenzenesulfonamide derivatives as BACE 1 inhibitors

Bioorg Med Chem. 2008 Dec 15;16(24):10190-7. doi: 10.1016/j.bmc.2008.10.059. Epub 2008 Oct 30.

Abstract

The pharmacophore model of arylpiperazine amide derivatives was built using Discovery Studio 2.0 software package and the best pharmacophore model (Hypo 1) was validated by Enrichment and ROC method (EF at 2%, 5% and 10% are 30.6, 12.2 and 7.7; AUC of the ROC curve is 0.93). According to the best pharmacophore model, 11 N-phenyl-1-arylamide, N-phenylbenzenesulfonamide derivatives, compounds 26-28, and 33a-g, were designed to be synthesized and their BACE 1 inhibitory activities were determined experimentally. Their theoretical results were in good agreement with the experimental values. Compound 33d, which displayed the highest BACE 1 activity (18.33+/-2.80 micromol/L) among these two series, was chosen to study the protein binding pattern and the result showed that it was in close contact with two essential catalytic aspartates (Asp32 and Asp228) of the BACE 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Computer Simulation
  • Drug Design
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Inhibitory Concentration 50
  • Models, Biological
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • Sulfonamides
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human