The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2013 Jan 15;23(2):466-71. doi: 10.1016/j.bmcl.2012.11.055. Epub 2012 Nov 29.

Abstract

In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology
  • Drug Discovery*
  • ERG1 Potassium Channel
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rats
  • Structure-Activity Relationship

Substances

  • Azepines
  • ERG1 Potassium Channel
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Amyloid Precursor Protein Secretases