Novel peptidomimetics as BACE-1 inhibitors: synthesis, molecular modeling, and biological studies

Bioorg Med Chem Lett. 2013 Jan 1;23(1):85-9. doi: 10.1016/j.bmcl.2012.11.011. Epub 2012 Nov 14.

Abstract

Aiming at identifying new scaffolds for BACE-1 inhibition devoid of the pharmacokinetic drawbacks of peptide-like structures, we investigated a series of novel peptidomimetics based on a 1,4-benzodiazepine (BDZ) core 1a-h and their seco-analogues 2a-d. We herein discuss synthesis, molecular modeling and in vitro studies which, starting from 1a, led to the seco-analogues (R)-2c and (S)-2d endowed with BACE-1 inhibition properties in the micromolar range both on the isolated enzyme and in cellular studies. These data can encourage to pursue these analogues as hits for the development of a new series of BACE-1 inhibitors active on whole-cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Benzodiazepines / chemistry
  • Binding Sites
  • Catalytic Domain
  • HEK293 Cells
  • Humans
  • Models, Chemical*
  • Molecular Docking Simulation
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry*
  • Peptidomimetics / metabolism
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transfection

Substances

  • Peptidomimetics
  • Protease Inhibitors
  • Benzodiazepines
  • Amyloid Precursor Protein Secretases