Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure

J Med Chem. 2012 Nov 8;55(21):9195-207. doi: 10.1021/jm3008823. Epub 2012 Sep 6.

Abstract

The structure-based design, synthesis, and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S(1)' active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Phthalic Acids / chemical synthesis*
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Amides
  • Indoles
  • Ligands
  • Phthalic Acids
  • Sulfonamides
  • Amyloid Precursor Protein Secretases

Associated data

  • PDB/4GID