Heparin Derivatives as Inhibitors of BACE-1, the Alzheimer's β-Secretase, with Reduced Activity against Factor Xa and Other Proteases

Heparan sulfate (HS) regulates processing of the amyloid precursor protein by the Alzheimer's β-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 inhibit...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-10, Vol.49 (20), p.6129-6132
Main Authors: Patey, Susannah J, Edwards, Elizabeth A, Yates, Edwin A, Turnbull, Jeremy E
Format: Article
Language:English
Subjects:
Alzheimer Disease - enzymology
Amyloid Precursor Protein Secretases
Animals
Anticoagulants - chemical synthesis
Anticoagulants - chemistry
Aspartic Acid Endopeptidases - antagonists & inhibitors
Aspartic Acid Endopeptidases - chemistry
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
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
Medical sciences
Neuropharmacology
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Renin - antagonists & inhibitors
Renin - chemistry
Structure-Activity Relationship
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Summary:Heparan sulfate (HS) regulates processing of the amyloid precursor protein by the Alzheimer's β-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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm051221o