Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897

Biochem Pharmacol. 2005 Feb 15;69(4):689-98. doi: 10.1016/j.bcp.2004.11.015. Epub 2005 Jan 7.


A primary pathological feature of Alzheimer's disease is beta-amyloid (Abeta)-containing plaques in brain and cerebral vasculature. Reductions in the formation of Abeta peptides by gamma-secretase inhibitors may be a viable therapy for reducing Abeta in Alzheimer's disease. Here we report on the effects of two orally active gamma-secretase inhibitors. BMS-289948 (4-chloro-N-(2,5-difluorophenyl)-N-((1R)-{4-fluoro-2-[3-(1H-imidazol-1-yl)propyl]phenyl}ethyl)benzenesulfonamide hydrochloride) and BMS-299897 (4-[2-((1R)-1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)-5-fluorophenyl]butanoic acid) markedly reduced both brain and plasma Abeta(1-40) in APP-YAC mice with ED(50) values of 86 and 22 mg/kg per os (po), respectively, for BMS-289948, and 30 and 16 mg/kg po, respectively, for BMS-299897. Both compounds also dose-dependently increased brain concentrations of APP carboxy-terminal fragments, consistent with inhibition of gamma-secretase. BMS-289948 and BMS-299897 (100 mg/kg po) reduced brain and plasma Abeta(1-40) rapidly (within 20min) and maximally within 3 h. BMS-299897 also dose-dependently reduced cortical, cerebrospinal fluid (CSF), and plasma Abeta in guinea pigs with ED(50) values of 30 mg/kg intraperitoneally, without affecting CSF levels of alpha-sAPP. The reductions in cortical Abeta correlated significantly with the reductions in both plasma (r(2) = 0.77) and CSF (r(2) = 0.61) Abeta. The decreases in Abeta were apparent at 3 and 6 h post-administration of BMS-299897, but not at 12h. These results demonstrate that BMS-289948 and BMS-299897 are orally bioavailable, functional gamma-secretase inhibitors with the ability to markedly reduce Abeta peptide concentrations in APP-YAC transgenic mice and in guinea pigs. These compounds may be useful pharmacologically for examining the effects of reductions in beta-amyloid peptides in both animal models and in Alzheimer's disease.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / analysis*
  • Amyloid beta-Peptides / blood
  • Animals
  • Aspartic Acid Endopeptidases
  • Brain Chemistry / drug effects
  • Butyrates / pharmacology*
  • Endopeptidases / drug effects*
  • Female
  • Guinea Pigs
  • Humans
  • Hydrocarbons, Halogenated / pharmacology*
  • Imidazoles / pharmacology*
  • Male
  • Mice
  • Peptide Fragments / analysis
  • Protease Inhibitors / pharmacology*
  • Sulfonamides / pharmacology*


  • 4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid
  • 4-chloro-N-(2,5-difluorophenyl)-N-((1R)-(4-fluoro-2-(3-(1H-imidazol-1-yl)propyl)phenyl)ethyl)benzenesulfonamide hydrochloride
  • Amyloid beta-Peptides
  • Butyrates
  • Hydrocarbons, Halogenated
  • Imidazoles
  • Peptide Fragments
  • Protease Inhibitors
  • Sulfonamides
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse