6 research outputs found
Molecular-Level Understanding of the Encapsulation and Dissolution of Poorly Water-Soluble Ibuprofen by Functionalized Organic Nanotubes Using Solid-State NMR Spectroscopy
A comprehensive study of the encapsulation
and dissolution of the poorly water-soluble drug ibuprofen (IBU) using
two types of organic nanotubes (ONT-1 and ONT-2) was conducted. ONT-1
and ONT-2 had similar inner and outer diameters, but these surfaces
were functionalized with different groups. IBU was encapsulated by
each ONT via solvent evaporation. The amount of IBU in the ONTs was
9.1 and 29.2 wt % for ONT-1 and ONT-2, respectively. Dissolution of
IBU from ONT-1 was very rapid, while from ONT-2 it was slower after
the initial burst release. One-dimensional (1D) <sup>1</sup>H, <sup>13</sup>C, and two-dimensional (2D) <sup>1</sup>H–<sup>13</sup>C solid-state NMR measurements using fast magic-angle spinning (MAS)
at a rate of 40 kHz revealed the molecular state of the encapsulated
IBU in each ONT. Extremely mobile IBU was observed inside the hollow
nanosapce of both ONT-1 and ONT-2 using <sup>13</sup>C MAS NMR with
a single pulse (SP) method. Interestingly, <sup>13</sup>C cross-polarization
(CP) MAS NMR demonstrated that IBU also existed on the outer surface
of both ONTs. The encapsulation ratios of IBU inside the hollow nanospaces
versus on the outer surfaces were calculated by waveform separation
to be approximately 1:1 for ONT-1 and 2:1 for ONT-2. Changes in <sup>13</sup>C chemical shifts showed the intermolecular interactions
between the carboxyl group of IBU and the amino group on the ONT-2
inner surface. The cationic ONT-2 could form the stronger electrostatic
interactions with IBU in the hollow nanosapce than anionic ONT-1.
On the other hand, 2D <sup>1</sup>H–<sup>13</sup>C NMR indicated
that the hydroxyl groups of the glucose unit on the outer surface
of the ONTs interacted with the carboxyl group of IBU in both ONT-1
and ONT-2. The changes in peak shape and chemical shift of the ONT
glucose group after IBU encapsulation were larger in ONT-2 than in
ONT-1, indicating a stronger interaction between IBU and the outer
surface of ONT-2. The smaller amount of IBU encapsulation and rapid
IBU dissolution from ONT-1 could be due to the weak interactions both
at the outer and inner surfaces. Meanwhile, the stronger interaction
between IBU and the inner surface of ONT-2 could suppress IBU dissolution,
although the IBU on the outer surface of ONT-2 was released soon after
dispersal in water. This study demonstrates that the encapsulation
amount and the dissolution rates of poorly water-soluble drugs, a
class which makes up the majority of new drug candidates, can be controlled
using the functional groups on the surfaces of ONTs by considering
the host–guest interactions
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
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