Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases

J Med Chem. 2006 Oct 5;49(20):6129-32. doi: 10.1021/jm051221o.

Abstract

Heparan sulfate (HS) regulates processing of the amyloid precursor protein by the Alzheimer's beta-secretase (BACE-1). An HS analogue, porcine intestinal mucosal heparin, was systematically modified at the principal positions of O-sulfation and N-sulfation/acetylation and tested for BACE-1 inhibitory and anti factor Xa activities. The derivative with the highest anti-BACE-1 to anti-Xa activity ratio contained N-acetyl and 2-O- and 6-O-sulfates and also exhibited attenuated activities against cathepsin-D and renin, two other structurally related aspartyl proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases
  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Cathepsin D / antagonists & inhibitors
  • Cathepsin D / chemistry
  • Cattle
  • Endopeptidases / chemistry*
  • Factor Xa / chemistry
  • Factor Xa Inhibitors*
  • Heparin / analogs & derivatives*
  • Heparin / chemical synthesis*
  • Heparin / chemistry
  • Heparitin Sulfate / analogs & derivatives*
  • Heparitin Sulfate / chemical synthesis*
  • Heparitin Sulfate / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Renin / antagonists & inhibitors
  • Renin / chemistry
  • Structure-Activity Relationship

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Protease Inhibitors
  • Heparin
  • Heparitin Sulfate
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Factor Xa
  • Aspartic Acid Endopeptidases
  • Renin
  • Cathepsin D