Design and synthesis of statine-containing BACE inhibitors

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4335-9. doi: 10.1016/j.bmcl.2003.09.037.

Abstract

Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.

MeSH terms

  • Alzheimer Disease / enzymology
  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Drug Design
  • Endopeptidases
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kinetics
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Enzyme Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE2 protein, human
  • BACE1 protein, human
  • statine