%0 Journal Article
%T Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease
%A Guriqbal S Basi
%A Susanna Hemphill
%A Elizabeth F Brigham
%A Anna Liao
%A Danielle L Aubele
%A Jeanne Baker
%A Robin Barbour
%A Michael Bova
%A Xiao-Hua Chen
%A Michael S Dappen
%A Tovah Eichenbaum
%A Erich Goldbach
%A Jon Hawkinson
%A Rose Lawler-Herbold
%A Kang Hu
%A Terence Hui
%A Jacek J Jagodzinski
%A Pamela S Keim
%A Dora Kholodenko
%A Lee H Latimer
%A Mike Lee
%A Jennifer Marugg
%A Matthew N Mattson
%A Scott McCauley
%A James L Miller
%A Ruth Motter
%A Linda Mutter
%A Martin L Neitzel
%A Huifang Ni
%A Lan Nguyen
%J Alzheimer's Research & Therapy
%D 2010
%I BioMed Central
%R 10.1186/alzrt60
%X In vitro assays monitoring inhibitor potencies at APP ¦Ã-site cleavage (equivalent to A¦Â40), and Notch ¦Å-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A¦Â production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A¦Â was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A¦Â reduction vs. Notch signaling endpoints in periphery.The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A¦Â production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A¦Â in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A¦Â was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.The principal pathological features of Alzheimer's disease (AD), comprised of neurof
%U http://alzres.com/content/2/6/36