Developing β-secretase inhibitors for treatment of Alzheimer's disease

J Neurochem. 2012 Jan;120 Suppl 1(Suppl 1):71-83. doi: 10.1111/j.1471-4159.2011.07476.x. Epub 2011 Nov 28.


β-Secretase (memapsin 2; BACE-1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenesis of Alzheimer's disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ levels in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Drug Delivery Systems / methods*
  • Drug Delivery Systems / trends
  • Humans
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use*
  • Treatment Outcome


  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases