Synthesis of potent beta-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies

Org Biomol Chem. 2003 Jul 21;1(14):2468-73. doi: 10.1039/b304842j.

Abstract

Several beta-secretase inhibitors were designed based on hydroxyethylamine dipeptide isostere (HDI) structures and were synthesized by a methodology using the aza-Payne rearragement and O,N-acyl transfer reactions to study their structure-activity relationships. Among these pseudopeptides, effective compounds were developed as the first beta-secretase inhibitors containing the HDI transition state mimic with potent enzyme inhibitory activity (IC50 < 100 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Amino Acid Sequence
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / genetics
  • Aza Compounds / chemistry
  • Dipeptides / chemistry*
  • Esterification
  • Ethylamines / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Isoenzymes
  • Molecular Mimicry
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Dipeptides
  • Ethylamines
  • Isoenzymes
  • Oligopeptides
  • Protease Inhibitors
  • Recombinant Proteins
  • Aspartic Acid Endopeptidases