Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease

J Med Chem. 2012 Nov 8;55(21):9156-69. doi: 10.1021/jm300598e. Epub 2012 Sep 11.

Abstract

A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Brain / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Oxazoles / chemical synthesis*
  • Oxazoles / pharmacokinetics
  • Oxazoles / pharmacology
  • Peptide Fragments / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Xanthenes / chemical synthesis*
  • Xanthenes / pharmacokinetics
  • Xanthenes / pharmacology

Substances

  • Amyloid beta-Peptides
  • Oxazoles
  • Peptide Fragments
  • Xanthenes
  • amyloid beta-protein (1-40)
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/4FRI
  • PDB/4FRJ
  • PDB/4FRK