Lead Optimization and Modulation
of hERG Activity
in a Series of Aminooxazoline Xanthene β‑Site Amyloid
Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
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Abstract
The
optimization of a series of aminooxazoline xanthene inhibitors
of β-site amyloid precursor protein cleaving enzyme 1 (BACE1)
is described. An early lead compound showed robust Aβ lowering
activity in a rat pharmacodynamic model, but advancement was precluded
by a low therapeutic window to QTc prolongation in cardiovascular
models consistent with in vitro activity on the hERG ion channel.
While the introduction of polar groups was effective in reducing hERG
binding affinity, this came at the expense of higher than desired
Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity
was achieved by lowering the polar surface area of the P3 substituent
while retaining polarity in the P2′ side chain. The introduction
of a fluorine in position 4 of the xanthene ring improved BACE1 potency
(5–10-fold). The combination of these optimized fragments resulted
in identification of compound <b>40</b>, which showed robust
Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction
in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety
in vivo