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P3‐315: Significant reduction of brain and CSF amyloid‐β in mice following acute administration of a brain‐penetrant BACE1 inhibitor
Author(s) -
Hajos-Korcsok Eva,
Nolan Charles,
Oborski Christine,
Lanyon Lorraine,
Liston Dane,
Ambroise Claude,
Fisher Katherine,
Noell Stephen,
Christoffersen Curt,
Grimwood Sarah,
Hannah Divine,
Bian Feng,
Liu Jianhua,
Nelson Frederick,
Lu Yasong,
Coffey Heather,
Ogilvie Kevin,
Coffman Karen,
Efremov Ivan,
Helal Christopher,
Brodney Michael,
O'Neill Brian
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1816
Subject(s) - in vivo , pharmacology , chemistry , amyloid precursor protein , in vitro , ic50 , genetically modified mouse , amyloid precursor protein secretase , potency , subcutaneous injection , transgene , biochemistry , endocrinology , alzheimer's disease , medicine , biology , disease , microbiology and biotechnology , gene
measures (in vitro-in vivo correlation, IVIVC) and identified the best IVIVC, and (3) analyzed the best IVIVC quantitatively to understand in vitro-in vivo translation. Results: Within the potency range of up to 2500 nM, the WT-WCA and mutant-WCA IC50’s are modestly correlated (R 1⁄4 0.8); both of them are only weakly correlated with EAA IC50 (R < 0.45). The IVIVC inspection found that free brain drug exposure (Cb,u) is more relevant than total brain exposure and that the EAA IC50 best predicts in vivo effect of brain Ab reduction. Further quantitative analyses of the brain Ab-Cb,u/EAA IC50 correlation suggested that the maximum brain Ab reduction under those experimental settings was about 70% and that 50% of reduction from baseline was achieved at Cb,u equivalent to EAA IC50. Conclusions: An IVIVC has been established among brain Ab reduction, free brain drug exposure, and enzyme activity assay IC50. This correlation is instrumental in expediting early discovery of BACE1 inhibitors.