Part 3: Notch-sparing γ-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones

Bioorg Med Chem Lett. 2016 May 1;26(9):2138-41. doi: 10.1016/j.bmcl.2016.03.077. Epub 2016 Mar 23.

Abstract

In search for novel lead compounds as γ-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-ones (I) were synthesized and evaluated for inhibitory effects on amyloid-β-peptide production and cleavage of the Notch1 receptor mediated by γ-secretase. Selected pyridopyrimidines, such as 1, 8, 9, 10, 11 and 16 are γ-secretase inhibitors that did not have an effect on Notch1 receptor processing.

Keywords: Alzheimer’s disease; Aminopyridopyrimidines; Aβ production; Notch-processing; γ-Secretase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Animals
  • Humans
  • Microsomes, Liver / metabolism
  • Peptide Fragments / antagonists & inhibitors
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*
  • Pyridones / chemical synthesis
  • Pyridones / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Rats
  • Receptor, Notch1 / metabolism*
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • NOTCH1 protein, human
  • Notch1 protein, rat
  • Peptide Fragments
  • Protease Inhibitors
  • Pyridones
  • Pyrimidines
  • Receptor, Notch1
  • amyloid beta-protein (1-40)
  • Amyloid Precursor Protein Secretases