1 research outputs found
Design and Synthesis of Ī²āSite Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of Ī²āAmyloid Peptides
The evaluation of a series of aminoisoindoles as Ī²-site
amyloid
precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery
of a clinical candidate drug for Alzheimerās disease, (<i>S</i>)-<b>32</b> (AZD3839), are described. The improvement
in permeability properties by the introduction of fluorine adjacent
to the amidine moiety, resulting in in vivo brain reduction of AĪ²40,
is discussed. Due to the basic nature of these compounds, they displayed
affinity for the human ether-a-go-go related gene (hERG) ion channel.
Different ways to reduce hERG inhibition and increase hERG margins
for this series are described, culminating in (<i>S</i>)-<b>16</b> and (<i>R</i>)-<b>41</b> showing large
in vitro margins with BACE1 cell IC<sub>50</sub> values of 8.6 and
0.16 nM, respectively, and hERG IC<sub>50</sub> values of 16 and 2.8
Ī¼M, respectively. Several compounds were advanced into pharmacodynamic
studies and demonstrated significant reduction of Ī²-amyloid
peptides in mouse brain following oral dosing