Discovery of gamma-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's disease

Bioorg Med Chem Lett. 2007 Jan 15;17(2):511-6. doi: 10.1016/j.bmcl.2006.10.011. Epub 2006 Oct 10.

Abstract

Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Area Under Curve
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Conformation
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Amyloid Precursor Protein Secretases