Purine derivatives as potent gamma-secretase modulators

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2279-82. doi: 10.1016/j.bmcl.2010.02.008. Epub 2010 Feb 6.

Abstract

The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Humans
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / metabolism
  • Purines / chemistry*
  • Purines / pharmacology
  • Purines / therapeutic use*
  • Receptors, Notch / metabolism
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Purines
  • Receptors, Notch
  • amyloid beta-protein (40-42)
  • Amyloid Precursor Protein Secretases