2 research outputs found
An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities
BACE1
inhibition to prevent Aβ peptide formation is considered
to be a potential route to a disease-modifying treatment for Alzheimer’s
disease. Previous efforts in our laboratory using a combined structure-
and property-based approach have resulted in the identification of
aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report
further optimization leading to the discovery of inhibitor <b>15</b> as an orally available and highly efficacious BACE1 inhibitor that
robustly reduces CSF and brain Aβ levels in both rats and nonhuman
primates. In addition, compound <b>15</b> exhibited low activity
on the hERG ion channel and was well tolerated in an integrated cardiovascular
safety model
Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
We have previously shown that hydroxyethylamines can
be potent
inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors
with CYP 3A4 inhibitory activities in this scaffold affords compounds
(e.g., <b>1</b>) with sufficient bioavailability and pharmacokinetic
profiles to reduce central amyloid-β peptide (Aβ) levels
in wild-type rats following oral dosing. In this article, we describe
further modifications of the P1-phenyl ring of the hydroxyethylamine
series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate
improved penetration into the CNS. Several of these compounds caused
robust reduction of Aβ levels in rat CSF and brain following
oral dosing, and compound <b>37</b> exhibited an improved cardiovascular
safety profile relative to <b>1</b>