Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase

J Med Chem. 2004 Jan 1;47(1):158-64. doi: 10.1021/jm0304008.

Abstract

The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases / chemistry*
  • Dipeptides / chemistry*
  • Drug Design
  • Endopeptidases
  • Ethylenes / chemical synthesis*
  • Ethylenes / chemistry
  • Humans
  • Models, Molecular
  • Molecular Mimicry
  • Phthalic Acids / chemical synthesis*
  • Phthalic Acids / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Structure-Activity Relationship

Substances

  • Amides
  • Dipeptides
  • Ethylenes
  • N-(1-(3,5-difluorobenzyl)-2-hydroxy-4-isobutylcarbamoylpentyl)-N',N'-dipropylisophthalamide
  • Phthalic Acids
  • Protease Inhibitors
  • hydroxyethylene
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human