Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human beta-secretase

J Med Chem. 2003 May 8;46(10):1799-802. doi: 10.1021/jm025619l.

Abstract

We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cell Line
  • Endopeptidases
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Molecular Mimicry
  • Oligopeptides / chemistry*
  • Structure-Activity Relationship

Substances

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