RT Journal Article
SR Electronic
T1 Studies to Investigate the in Vivo Therapeutic Window of the γ-Secretase Inhibitor <em>N</em><sup>2</sup>-[(2<em>S</em>)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-<em>N</em><sup>1</sup>-[(7<em>S</em>)-5-methyl-6-oxo-6,7-dihydro-5<em>H</em>-dibenzo[<em>b</em>,<em>d</em>]azepin-7-yl]-<span class="sc">l</span>-alaninamide (LY411,575) in the CRND8 Mouse
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1133
OP 1143
DO 10.1124/jpet.106.111716
VO 319
IS 3
A1 Lynn A. Hyde
A1 Nansie A. McHugh
A1 Joseph Chen
A1 Qi Zhang
A1 Denise Manfra
A1 Amin A. Nomeir
A1 Hubert Josien
A1 Thomas Bara
A1 John W. Clader
A1 Lili Zhang
A1 Eric M. Parker
A1 Guy A. Higgins
YR 2006
UL http://jpet.aspetjournals.org/content/319/3/1133.abstract
AB 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 (&gt;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.