Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. Epub 2015 Jan 8.

Abstract

The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

Keywords: 3-Azaxanthene; Alzheimer’s disease (AD); Aminooxazoline; Amyloid; Aβ peptides; Xanthene; β-Secretase (BACE1).

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cell Line
  • HEK293 Cells
  • Humans
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology*
  • Rats
  • Xanthenes / chemical synthesis
  • Xanthenes / chemistry*
  • Xanthenes / pharmacology*

Substances

  • Protease Inhibitors
  • Xanthenes
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human