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 Lamb, Donna Barten, Kevin Felsenstein, Ian McDonald, Kumar Srinivasan, Ben Munoz, Steven L. Wagner

Research output: Contribution to journalArticle

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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

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid
Cerebrospinal fluid
Brain
Cerebrospinal Fluid
Plasmas
Alzheimer Disease
Peptides
Guinea Pigs
Aptitude
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
Transgenic Mice
Animals
Animal Models

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anderson, J. J., Holtz, G., Baskin, P. P., Turner, M., Rowe, B., Wang, 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

Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897. / Anderson, Jeffery J.; Holtz, Greg; Baskin, Patricia P.; Turner, Mary; Rowe, Blake; Wang, Bowei; Kounnas, Maria Z.; Lamb, Bruce; Barten, Donna; Felsenstein, Kevin; McDonald, Ian; Srinivasan, Kumar; Munoz, Ben; Wagner, Steven L.

In: Biochemical Pharmacology, Vol. 69, No. 4, 15.02.2005, p. 689-698.

Research output: Contribution to journalArticle

Anderson, JJ, Holtz, G, Baskin, PP, Turner, M, Rowe, B, Wang, B, Kounnas, MZ, Lamb, B, Barten, D, Felsenstein, K, McDonald, I, Srinivasan, K, Munoz, B & Wagner, SL 2005, 'Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897', Biochemical Pharmacology, vol. 69, no. 4, pp. 689-698. https://doi.org/10.1016/j.bcp.2004.11.015
Anderson, Jeffery J. ; Holtz, Greg ; Baskin, Patricia P. ; Turner, Mary ; Rowe, Blake ; Wang, Bowei ; Kounnas, Maria Z. ; Lamb, Bruce ; Barten, Donna ; Felsenstein, Kevin ; McDonald, Ian ; Srinivasan, Kumar ; Munoz, Ben ; Wagner, Steven L. / Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897. In: Biochemical Pharmacology. 2005 ; Vol. 69, No. 4. pp. 689-698.
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