BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease

J Med Chem. 2018 Feb 8;61(3):619-637. doi: 10.1021/acs.jmedchem.7b00393. Epub 2017 Aug 8.


The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.

Publication types

  • 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 / chemistry
  • Animals
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Humans
  • Molecular Targeted Therapy / methods*
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use


  • Protease Inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Amyloid Precursor Protein Secretases