Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1361-5. doi: 10.1016/j.bmcl.2009.01.036. Epub 2009 Jan 19.

Abstract

The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.

Publication types

  • Comparative Study

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites / physiology
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Humans
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Protein Structure, Tertiary / physiology
  • Structure-Activity Relationship

Substances

  • Macrocyclic Compounds
  • OM99-2
  • Oligopeptides
  • Peptide Fragments
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human