Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3457-60. doi: 10.1016/j.bmcl.2004.04.068.

Abstract

A new series of bis-statine based peptidomimetic inhibitors of human beta-secretase (BACE 1) was developed by structure-based modification of the three regions to the initial lead 3: an N-terminus, a central bis-statine core, and a C-terminus. Introduction of a 4-aminomethylbenzoic acid on the C-terminus resulted in a potent BACE 1 inhibitor with an IC50 value of 21 nM. The general requirements for the optimal substrate-enzyme interaction are disclosed herein.

MeSH terms

  • 4-Aminobenzoic Acid / chemistry
  • 4-Aminobenzoic Acid / pharmacology
  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cell Line
  • Endopeptidases
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Fluorescence Resonance Energy Transfer / methods
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Mimicry
  • Peptides / chemistry
  • Peptides / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • para-Aminobenzoates*

Substances

  • Amino Acids
  • Enzyme Inhibitors
  • Peptides
  • para-Aminobenzoates
  • 4-aminomethylbenzoic acid
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • 4-Aminobenzoic Acid
  • statine