Design and Preparation
of a Potent Series of Hydroxyethylamine Containing β-Secretase
Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
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Abstract
A series of potent hydroxyethyl amine (HEA) derived inhibitors
of β-site APP cleaving enzyme (BACE1) was optimized to address
suboptimal pharmacokinetics and poor CNS partitioning. This work identified
a series of benzodioxolane analogues that possessed improved metabolic
stability and increased oral bioavailability. Subsequent efforts focused
on improving CNS exposure by limiting susceptibility to Pgp-mediated
efflux and identified an inhibitor which demonstrated robust and sustained
reduction of CNS β-amyloid (Aβ) in Sprague–Dawley
rats following oral administration