6 research outputs found
Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization
β-Secretase
(BACE1) has an essential role in the production
of amyloid β peptides that accumulate in patients with Alzheimer’s
disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying
approach for the treatment of AD. Our hit-to-lead efforts led to a
cellular potent 1,3-dihydro-oxazine <b>6</b>, which however
inhibited hERG and showed high P-gp efflux. The close analogue of
5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction
of electron withdrawing groups at the 6-position improved potency
and also mitigated P-gp efflux and hERG inhibition. Changing to a
pyrazine followed by optimization of substituents on both the oxazine
and the pyrazine culminated in <b>24</b> with robust Aβ
reduction in vivo at low doses as well as reduced CYP2D6 inhibition.
On the basis of the X-ray analysis and the QM calculation of given
dihydro-oxazines, we reasoned that the substituents at the 6-position
as well as the 5-fluorine on the oxazine would stabilize a bioactive
conformation to increase potency
Discovery of Potent and Centrally Active 6‑Substituted 5‑Fluoro-1,3-dihydro-oxazine β‑Secretase (BACE1) Inhibitors via Active Conformation Stabilization
β-Secretase
(BACE1) has an essential role in the production
of amyloid β peptides that accumulate in patients with Alzheimer’s
disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying
approach for the treatment of AD. Our hit-to-lead efforts led to a
cellular potent 1,3-dihydro-oxazine <b>6</b>, which however
inhibited hERG and showed high P-gp efflux. The close analogue of
5-fluoro-oxazine <b>8</b> reduced P-gp efflux; further introduction
of electron withdrawing groups at the 6-position improved potency
and also mitigated P-gp efflux and hERG inhibition. Changing to a
pyrazine followed by optimization of substituents on both the oxazine
and the pyrazine culminated in <b>24</b> with robust Aβ
reduction in vivo at low doses as well as reduced CYP2D6 inhibition.
On the basis of the X-ray analysis and the QM calculation of given
dihydro-oxazines, we reasoned that the substituents at the 6-position
as well as the 5-fluorine on the oxazine would stabilize a bioactive
conformation to increase potency
Discovery of Imidazo[1,2‑<i>b</i>]pyridazine Derivatives: Selective and Orally Available Mps1 (TTK) Kinase Inhibitors Exhibiting Remarkable Antiproliferative Activity
Monopolar
spindle 1 (Mps1) is an attractive oncology target due
to its high expression level in cancer cells as well as the correlation
of its expression levels with histological grades of cancers. An imidazoÂ[1,2-<i>a</i>]Âpyrazine <b>10a</b> was identified during an HTS
campaign. Although <b>10a</b> exhibited good biochemical activity,
its moderate cellular as well as antiproliferative activities needed
to be improved. The cocrystal structure of an analogue of <b>10a</b> guided our lead optimization to introduce substituents at the 6-position
of the scaffold, giving the 6-aryl substituted <b>21b</b> which
had improved cellular activity but no oral bioavailability in rat.
Property-based optimization at the 6-position and a scaffold change
led to the discovery of the imidazoÂ[1,2-<i>b</i>]Âpyridazine-based <b>27f</b>, an extremely potent (cellular Mps1 IC<sub>50</sub> =
0.70 nM, A549 IC<sub>50</sub> = 6.0 nM), selective Mps1 inhibitor
over 192 kinases, which could be orally administered and was active
in vivo. This <b>27f</b> demonstrated remarkable antiproliferative
activity in the nanomolar range against various tissue cancer cell
lines
Rational Design of Novel 1,3-Oxazine Based β‑Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P‑gp Efflux Leading to Robust Aβ Reduction in the Brain
Accumulation of Aβ
peptides is a hallmark of Alzheimer’s
disease (AD) and is considered a causal factor in the pathogenesis
of AD. β-Secretase (BACE1) is a key enzyme responsible for producing
Aβ peptides, and thus agents that inhibit BACE1 should be beneficial
for disease-modifying treatment of AD. Here we describe the discovery
and optimization of novel oxazine-based BACE1 inhibitors by lowering
amidine basicity with the incorporation of a double bond to improve
brain penetration. Starting from a 1,3-dihydrooxazine lead <b>6</b> identified by a hit-to-lead SAR following HTS, we adopted a p<i>K</i><sub>a</sub> lowering strategy to reduce the P-gp efflux
and the high hERG potential leading to the discovery of <b>15</b> that produced significant Aβ reduction with long duration
in pharmacodynamic models and exhibited wide safety margins in cardiovascular
safety models. This compound improved the brain-to-plasma ratio relative
to <b>6</b> by reducing P-gp recognition, which was demonstrated
by a P-gp knockout mouse model
Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125)
Monopolar spindle 1 (Mps1) is essential
for centrosome duplication, the spindle assembly check point, and
the maintenance of chromosomal instability. Mps1 is highly expressed
in cancer cells, and its expression levels correlate with the histological
grades of cancers. Thus, selective Mps1 inhibitors offer an attractive
opportunity for the development of novel cancer therapies. To design
novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone
(<b>4</b>, SP600125) and its crystal structure bound to JNK1.
Our design efforts led to the identification of indazole-based lead <b>6</b> with an Mps1 IC<sub>50</sub> value of 498 nM. Optimization
of the 3- and 6-positions on the indazole core of <b>6</b> resulted
in <b>23c</b> with improved Mps1 activity (IC<sub>50</sub> =
3.06 nM). Finally, application of structure-based design using the
X-ray structure of <b>23d</b> bound to Mps1 culminated in the
discovery of <b>32a</b> and <b>32b</b> with improved potency
for cellular Mps1 and A549 lung cancer cells. Moreover, <b>32a</b> and <b>32b</b> exhibited reasonable selectivities over 120
and 166 kinases, respectively
Diaminopyridine-Based Potent and Selective Mps1 Kinase Inhibitors Binding to an Unusual Flipped-Peptide Conformation
Monopolar spindle 1 (Mps1) is an attractive cancer drug
target
due to the important role that it plays in centrosome duplication,
the spindle assembly checkpoint, and the maintenance of chromosomal
stability. A design based on JNK inhibitors with an aminopyridine
scaffold and subsequent modifications identified diaminopyridine <b>9</b> with an IC<sub>50</sub> of 37 nM. The X-ray structure of <b>9</b> revealed that the Cys604 carbonyl group of the hinge region
flips to form a hydrogen bond with the aniline NH group in <b>9</b>. Further optimization of <b>9</b> led to <b>12</b> with
improved cellular activity, suitable pharmacokinetic profiles, and
good in vivo efficacy in the mouse A549 xenograft model. Moreover, <b>12</b> displayed excellent selectivity over 95 kinases, indicating
the contribution of its unusual flipped-peptide conformation to its
selectivity