Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4740-4. doi: 10.1016/j.bmcl.2012.05.072. Epub 2012 Jun 6.


A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Propanol / chemical synthesis*
  • 2-Propanol / metabolism
  • 2-Propanol / pharmacology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Blood-Brain Barrier / metabolism
  • Cathepsin D / antagonists & inhibitors
  • Chemical Phenomena
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship


  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Cathepsin D
  • 2-Propanol