Small-molecule BACE1 inhibitors: a patent literature review (2006 - 2011)

Expert Opin Ther Pat. 2012 May;22(5):511-40. doi: 10.1517/13543776.2012.681302. Epub 2012 Apr 19.


Introduction: Alzheimer's disease is a devastating neurodegenerative disorder for which no disease-modifying therapy exists. The amyloid hypothesis, which implicates Aβ as the toxin initiating a biological cascade leading to neurodegeneration, is the most prominent theory concerning the underlying cause of the disease. BACE1 is one of two aspartyl proteinases that generate Aβ, thus inhibition of BACE1 has the potential to ameliorate the progression of Alzheimer's disease by abating the production of Aβ.

Areas covered: This review chronicles small-molecule BACE1 inhibitors as described in the patent literature between 2006 and 2011 and their potential use as disease-modifying treatments for Alzheimer's disease. Over the past half a dozen years, numerous BACE1 inhibitors have been published in the patent applications, but often these contain a paltry amount of pertinent biological data (e.g. potency, selectivity, and efficacy). Fortunately, numerous relevant publications containing important data have appeared in the journal literature during this period. The goal in this effort was to create an amalgam of the two records to add value to this review.

Expert opinion: The pharmaceutical industry has made tremendous progress in the development of small-molecule BACE1 inhibitors that lower Aβ in the central nervous system. Assuming the amyloid hypothesis is veracious, we anticipate a disease-modifying therapy to combat Alzheimer's disease is near.

Publication types

  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Brain / drug effects*
  • Brain / enzymology
  • Brain / pathology
  • Drug Design
  • Humans
  • Legislation, Drug
  • Molecular Structure
  • Patents as Topic
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Amyloid beta-Peptides
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human