The evolution of amidine-based brain penetrant BACE1 inhibitors

Bioorg Med Chem Lett. 2014 May 1;24(9):2033-45. doi: 10.1016/j.bmcl.2014.03.025. Epub 2014 Mar 20.


Beta site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.

Keywords: Alzheimer’s; Amyloid; BACE; BACE1; Inhibitor.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amidines / chemistry
  • Amidines / pharmacokinetics*
  • Amidines / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Brain / drug effects
  • Brain / metabolism*
  • Drug Discovery / methods
  • Humans
  • Models, Molecular


  • Amidines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human