Discovery of potent iminoheterocycle BACE1 inhibitors

Bioorg Med Chem Lett. 2014 Dec 1;24(23):5455-9. doi: 10.1016/j.bmcl.2014.10.006. Epub 2014 Oct 23.


The synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.

Keywords: Alzheimer’s disease; Aspartyl protease inhibitors; BACE; Structure-based drug design; β-Secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid Precursor Protein Secretases / therapeutic use*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Aspartic Acid Endopeptidases / therapeutic use*
  • Drug Design
  • Drug Discovery
  • Models, Molecular
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship


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