Premium
P1‐336: Novel BACE1 inhibitor, E2609, lowers Aβ levels in the cerebrospinal fluid and plasma in nonhuman primates
Author(s) -
Lucas Fiona,
Fukushima Tatsuto,
Nozaki Yoshitane
Publication year - 2012
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.2012.05.2022
Subject(s) - pharmacokinetics , cerebrospinal fluid , pharmacology , pharmacodynamics , in vivo , oral administration , chemistry , medicine , biology , microbiology and biotechnology
Background: Alzheimer’s disease (AD) is characterized by accumulation of Ab-containing plaques and tau-containing neurofibrillary tangles in the brain. The production of pathological Ab peptides, Ab1-42 in particular, is thought to be an initiating event in AD. BACE1 cleavage of the amyloid precursor protein is the first step in the production of Ab and is therefore a prime target to block the pathogenic amyloid cascade leading to AD and potentially modify the disease progression. We have developed a potent small molecule, the orally bioavailable BACE1 inhibitor, E2609, (cell-based assay IC 50 w7 nmol/L) that has been shown to reduce Ab production in the plasma, brain, and cerebrospinal fluid (CSF) of rodents. Methods: The pharmacokinetic and pharmacodynamic relationship of E2609 was examined in cisterna magna ported cynomolgus monkeys. Plasma and CSF were sampled serially over 72 hours post single oral administration of E2609 so that the temporal dynamics of Ab in plasma and CSF could be evaluated in detail. Plasma pharmacokinetics of E2609 was linked to Ab levels