Investigation of α-phenylnorstatine and α-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors

Bioorg Med Chem. 2011 Jan 1;19(1):145-55. doi: 10.1016/j.bmc.2010.11.042. Epub 2010 Nov 26.


Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacology*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*


  • Phenylbutyrates
  • Protease Inhibitors
  • 3-amino-2-hydroxy-4-phenylbutanoic acid
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human