Rational design and synthesis of selective BACE-1 inhibitors

Bioorg Med Chem Lett. 2004 Feb 9;14(3):601-4. doi: 10.1016/j.bmcl.2003.11.061.

Abstract

An effective approach for enhancing the selectivity of beta-site amyloid precursor protein cleaving enzyme (BACE 1) inhibitors is developed based on the unique features of the S1' pocket of the enzyme. A series of low molecular weight (<600) compounds were synthesized with different moieties at the P1' position. The selectivity of BACE 1 inhibitors versus cathepsin D and renin was enhanced 120-fold by replacing the hydrophobic propyl group with a hydrophilic propionic acid group.

Publication types

  • Comparative Study

MeSH terms

  • Alzheimer Disease / enzymology*
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cathepsin D / antagonists & inhibitors
  • Drug Design*
  • Endopeptidases
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Molecular Weight
  • Propionates / chemistry
  • Renin / antagonists & inhibitors
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Propionates
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • Renin
  • BACE1 protein, human
  • Cathepsin D
  • propionic acid