Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897

Jeffery J. Anderson, Greg Holtz, Patricia P. Baskin, Mary Turner, Blake Rowe, Bowei Wang, Maria Z. Kounnas, Bruce T. Lamb, Donna Barten, Kevin Felsenstein, Ian McDonald, Kumar Srinivasan, Ben Munoz, Steven L. Wagner

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98 Scopus citations

Abstract

A primary pathological feature of Alzheimer's disease is β-amyloid (Aβ)-containing plaques in brain and cerebral vasculature. Reductions in the formation of Aβ peptides by γ-secretase inhibitors may be a viable therapy for reducing Aβ in Alzheimer's disease. Here we report on the effects of two orally active γ-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 Aβ1-40 in APP-YAC mice with ED50 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 γ-secretase. BMS-289948 and BMS-299897 (100 mg/kg po) reduced brain and plasma Aβ1-40 rapidly (within 20 min) and maximally within 3 h. BMS-299897 also dose-dependently reduced cortical, cerebrospinal fluid (CSF), and plasma Aβ in guinea pigs with ED 50 values of 30 mg/kg intraperitoneally, without affecting CSF levels of α-sAPP. The reductions in cortical Aβ correlated significantly with the reductions in both plasma (r2 = 0.77) and CSF (r2 = 0.61) Aβ. The decreases in Aβ were apparent at 3 and 6 h post-administration of BMS-299897, but not at 12 h. These results demonstrate that BMS-289948 and BMS-299897 are orally bioavailable, functional γ-secretase inhibitors with the ability to markedly reduce Aβ peptide concentrations in APP-YAC transgenic mice and in guinea pigs. These compounds may be useful pharmacologically for examining the effects of reductions in β-amyloid peptides in both animal models and in Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)689-698
Number of pages10
JournalBiochemical Pharmacology
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2005
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Proteolytic processing
  • Secretase
  • β-Amyloid
  • γ-Secretase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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    Anderson, J. J., Holtz, G., Baskin, P. P., Turner, M., Rowe, B., Wang, B., Kounnas, M. Z., Lamb, B. T., Barten, D., Felsenstein, K., McDonald, I., Srinivasan, K., Munoz, B., & Wagner, S. L. (2005). Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897. Biochemical Pharmacology, 69(4), 689-698. https://doi.org/10.1016/j.bcp.2004.11.015