Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4245-9. doi: 10.1016/j.bmcl.2015.07.101. Epub 2015 Aug 7.

Abstract

Novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives were designed, synthesized, and evaluated as γ-secretase modulators (GSMs). An optimization study of this series resulted in the identification of (R)-11j, which showed a potent Aβ42-lowering effect, high bioavailability and good blood-brain barrier permeability in mice. Oral administration of (R)-11j significantly reduced brain Aβ42 in mice at a dose of 10 mg/kg.

Keywords: Alzheimer’s disease; Amyloid beta; γ-Secretase modulators.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Pyridines / administration & dosage
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship
  • Triazoles / administration & dosage
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Pyridines
  • Triazoles
  • Amyloid Precursor Protein Secretases