7 research outputs found
Inhibitors of β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (<i>S</i>)‑7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′<i>H</i>‑spiro[chromeno[2,3‑<i>b</i>]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)
We
have previously shown that the aminooxazoline xanthene scaffold
can generate potent and orally efficacious BACE1 inhibitors although
certain of these compounds exhibited potential hERG liabilities. In
this article, we describe 4-aza substitution on the xanthene core
as a means to increase BACE1 potency while reducing hERG binding affinity.
Further optimization of the P3 and P2′ side chains resulted
in the identification of <b>42</b> (AMG-8718), a compound with
a balanced profile of BACE1 potency, hERG binding affinity, and Pgp
recognition. This compound produced robust and sustained reductions
of CSF and brain Aβ levels in a rat pharmacodynamic model and
exhibited significantly reduced potential for QTc elongation in a
cardiovascular safety model
Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
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
Sulfonamides as Selective Na<sub>V</sub>1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities
Several reports have recently emerged
regarding the identification
of heteroarylsulfonamides as Na<sub>V</sub>1.7 inhibitors that demonstrate
high levels of selectivity over other Na<sub>V</sub> isoforms. The
optimization of a series of internal Na<sub>V</sub>1.7 leads that
address a number of metabolic liabilities including bioactivation,
PXR activation, as well as CYP3A4 induction and inhibition led to
the identification of potent and selective inhibitors that demonstrated
favorable pharmacokinetic profiles and were devoid of the aforementioned
liabilities. The key to achieving this within a series prone to transporter-mediated
clearance was the identification of a small range of optimal cLogD
values and the discovery of subtle PXR SAR that was not lipophilicity
dependent. This enabled the identification of compound <b>20</b>, which was advanced into a target engagement pharmacodynamic model
where it exhibited robust reversal of histamine-induced scratching
bouts in mice
Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
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
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>