Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors

Bioorg Med Chem Lett. 2011 Apr 1;21(7):1942-7. doi: 10.1016/j.bmcl.2011.02.038. Epub 2011 Feb 15.

Abstract

This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Benzylamines / chemical synthesis
  • Benzylamines / chemistry*
  • Benzylamines / pharmacology*
  • Crystallography, X-Ray
  • Cyclic S-Oxides / chemical synthesis
  • Cyclic S-Oxides / chemistry*
  • Cyclic S-Oxides / pharmacology*
  • Cyclization
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Benzylamines
  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human