Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6386-91. doi: 10.1016/j.bmcl.2009.09.061. Epub 2009 Sep 19.

Abstract

Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / genetics
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / genetics
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human