Studies to Investigate the in Vivo Therapeutic Window 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) in the CRND8 Mouse

摘要

Accumulation of amyloid beta-peptide (A beta) is considered a key step in the etiology of Alzheimer's disease.Abeta is produced by sequential cleavage of the amyloid precursor protein by beta-and gamma-secre-tase enzymes.Consequently,inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease.Pre-clinically,several gamma-secretase inhibitors have been shown to reduce plasma and brain Abeta,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 (ED_(50) approx=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.