Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease

J Med Chem. 2008 Dec 11;51(23):7348-51. doi: 10.1021/jm801252w.

Abstract

SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Molecular Conformation
  • Receptor, Notch1 / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Receptor, Notch1
  • Sulfonamides
  • Thiophenes
  • begacestat
  • Amyloid Precursor Protein Secretases