Studies to Investigate the in Vivo Therapeutic Window of the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) in the CRND8 Mouse

  1. Lynn A. Hyde,
  2. Nansie A. McHugh1,
  3. Joseph Chen,
  4. Qi Zhang,
  5. Denise Manfra,
  6. Amin A. Nomeir,
  7. Hubert Josien,
  8. Thomas Bara,
  9. John W. Clader,
  10. Lili Zhang,
  11. Eric M. Parker and
  12. Guy A. Higgins2
  1. Departments of Neurobiology (L.A.H., N.A.M., J.C., Q.Z., L.Z., E.M.P., G.A.H.), Inflammation and Infectious Diseases (D.M.), Drug Metabolism and Pharmacokinetics (A.A.N.), and Chemical Research (H.J., T.B., J.W.C.), Schering Plough Research Institute, Kenilworth, New Jersey
  1. Address correspondence to:
    Dr. Lynn A. Hyde, Schering Plough Research Institute, K15-2-2600, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail: lynn.hyde{at}spcorp.com

Abstract

Accumulation of amyloid β-peptide (Aβ) is considered a key step in the etiology of Alzheimer's disease. Aβ is produced by sequential cleavage of the amyloid precursor protein by β- and γ-secretase enzymes. Consequently, inhibition of γ-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several γ-secretase inhibitors have been shown to reduce plasma and brain Aβ, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of γ-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Aβ40 in young (preplaque) transgenic CRND8 mice (ED50 ≈ 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Aβ40 by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Aβ levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel γ-secretase inhibitors.

Footnotes

  • Some of this work has been previously published in abstract form: Hyde LA, McHugh NA, Chen J, Zhang Q, Josien H, Clader J, Zhang L, Parker EM, and Higgins GA (2004) Use of a rapid in vivo screen to characterize mechanism-based side-effects following subchronic gamma secretase inhibition in transgenic CRND8 mice (abstract 675.2), in 2004 Abstract Viewer/Itinerary Planner; 2004 Oct 23–27; online. Society for Neuroscience, Washington, D.C.; and Hyde LA, Manfra D, McHugh NA, Zhang Q, Engstrom L, Pinzon-Ortiz MC, Chen J, Josien H, Clader J, Zhang L, Parker EM, and Higgins GA (2004) Rapid in vivo assessment of therapeutic window of two gamma secretase inhibitors in transgenic CRND8 mice. Neurobiol Aging25:S578.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.111716.

  • ABBREVIATIONS: AD, Alzheimer's disease; Aβ, amyloid β-peptide; APP, amyloid precursor protein; LY411,575, N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide; DAPT, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester; BMS-299897, 2-[(1R)-1-[[(4-chlorophenyl)-sulfonyl](2,5-difluorophenyl)amino]ethyl]-5-fluoro-benzenepropanoic acid; Compound E, (2S)-2-{[(3,5-diflurophenyl)acetyl]amino}-N-[(3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide; MRK-560, N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide; LY450,139, 2(S)-hydroxy-3-methyl-N-[1(S)-methyl-2-oxo-2-[(2,3,4,5-tetrahydro-3-methyl-2-oxo-1H-3-benzazepine-1(S)-yl)amino]ethyl]butanamide; PAS, periodic acid-Schiff; BLD, below the level of detection; LY-D, N2-[(2R)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7R)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl-l-alaninamide.

  • ↵1 Current affiliation: Huntingdon Life Sciences, East Millstone, New Jersey.

  • ↵2 Current affiliation: NPS Pharmaceuticals, Toronto, Ontario, Canada.

    • Received July 28, 2006.
    • Accepted August 30, 2006.
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  1. Published online before print August 31, 2006, doi: 10.1124/jpet.106.111716 JPET December 2006 vol. 319 no. 3 1133-1143
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