9 research outputs found
Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease
A structure- and property-based drug design approach
was employed
to identify aminooxazoline xanthenes as potent and selective human
β-secretase inhibitors. These compounds exhibited good isolated
enzyme, cell potency, and selectivity against the structurally related
aspartyl protease cathepsin D. Our efforts resulted in the identification
of a potent, orally bioavailable CNS penetrant compound that exhibited
in vivo efficacy. A single oral dose of compound <b>11a</b> resulted
in a significant reduction of CNS Aβ40 in naive rats
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
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
Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors
The
high expression of proviral insertion site of Moloney murine leukemia
virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic
malignancies, is believed to play a role in promoting cell survival
and proliferation while suppressing apoptosis. The three isoforms
of Pim protein appear largely redundant in their oncogenic functions.
Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell
active pan-Pim inhibitors have proven difficult to develop because
Pim-2 has a low <i>K</i><sub>m</sub> for ATP and therefore
requires a very potent inhibitor to effectively block the kinase activity
at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones
as potent and selective pan-Pim inhibitors. In particular, compound <b>17</b> is orally efficacious in a mouse xenograft model (KMS-12
BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg
QD upon oral dosing
Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors
In nonsmall cell lung cancer (NSCLC),
the threonine<sup>790</sup>–methionine<sup>790</sup> (T790M)
point mutation of EGFR kinase
is one of the leading causes of acquired resistance to the first generation
tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib.
Herein, we describe the optimization of a series of 7-oxopyridoÂ[2,3-<i>d</i>]Âpyrimidinyl-derived irreversible inhibitors of EGFR kinase.
This led to the discovery of compound <b>24</b> which potently
inhibits gefitinib-resistant EGFR<sup>L858R,T790M</sup> with 100-fold
selectivity over wild-type EGFR. Compound <b>24</b> displays
strong antiproliferative activity against the H1975 nonsmall cell
lung cancer cell line, the first line mutant HCC827 cell line, and
promising antitumor activity in an EGFR<sup>L858R,T790M</sup> driven
H1975 xenograft model sparing the side effects associated with the
inhibition of wild-type EGFR
A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase
β-Secretase inhibitors are potentially disease-modifying
treatments for Alzheimer's disease. Previous efforts in our laboratory
have resulted in hydroxyethylamine-derived inhibitors such as <b>1</b> with low nanomolar potency against β-site amyloid
precursor protein cleaving enzyme (BACE). When dosed intravenously,
compound <b>1</b> was also shown to significantly reduce Aβ<sub>40</sub> levels in plasma, brain, and cerebral spinal fluid. Herein,
we report further optimizations that led to the discovery of inhibitor <b>16</b> as a novel, potent, and orally efficacious BACE inhibitor
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>