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

Accumulation of amyloid beta-peptide (A beta) is considered a key step in the etiology of Alzheimer's disease. A beta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several gamma-secretase inhibitors have been shown to reduce plasma and brain A beta, 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 gamma-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the gamma-secretase inhibitor N-2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N-1-[(7S)5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d] azepin-7-yl]-L-alaninamide (LY411,575) reduced cortical A beta(40) in young (preplaque) transgenic CRND8 mice (ED50 approximate to 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 A beta(40) 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 A beta 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 gamma-secretase inhibitors.