13 research outputs found
Dose-dependent intracellular accumulation of test ERAs in sandwich-cultured human hepatocytes.
<p>Ambrisentan displayed the lowest intracellular accumulation followed by bosentan, sitaxsentan, and macitentan. Data are presented as mean (±SD) micromolar (µM) concentration; n = 3 donors; *P<0.05 vs. corresponding intracellular accumulation value for ambrisentan at the same test concentration.</p
Uptake of bosentan and macitentan into human hepatocytes.
<p>ERAs were evaluated either in the absence or presence of the transporter inhibitors rifampicin (40 µM) and cyclosporin A (5 µM). Data presented as mean (±SD) pmol/million cells; n = 4 donors; *P<0.05 for comparisons indicated.</p
Effect of Ambrisentan, Bosentan, Sitaxsentan, and Macitentan on Hepatic Uptake and Efflux Transporters.
a<p>Data presented as mean ± standard deviation for 3 independent studies performed in duplicate;</p>b<p>Data presented for a single experiment preformed in duplicate;</p>c<p>Data previously reported <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087548#pone.0087548-Ray1" target="_blank">[35]</a>. Ambrisentan, bosentan, and macitentan were tested in concentrations ranging from 0.14–100 µM.</p><p>ND = not determined.</p
d<sub>8</sub>-Taurocholate (d<sub>8</sub>-TCA) total (A) and cellular (B) accumulation in sandwich-cultured human hepatocytes exposed to ambrisentan, bosentan and macitentan.
<p>Bosentan and macitentan treatment resulted in a dose-dependent reduction in total accumulation of d<sub>8</sub>-TCA. Ambrisentan, bosentan and macitentan treatment each resulted in a dose-dependent reduction in cellular accumulation of d<sub>8</sub>-TCA. Data presented as mean (±SD) expressed as percent of control treated; n = 3 donors; *P<0.05 bosentan vs. control; # P<0.05 macitentan vs. control.</p
Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR‑2 (SLC19A3)
The
biguanide metformin is widely used as first-line therapy for
the treatment of type 2 diabetes. Predominately a cation at physiological
pH’s, metformin is transported by membrane transporters, which
play major roles in its absorption and disposition. Recently, our
laboratory demonstrated that organic cation transporter 1, OCT1, the
major hepatic uptake transporter for metformin, was also the primary
hepatic uptake transporter for thiamine, vitamin B1. In this study,
we tested the reverse, i.e., that metformin is a substrate of thiamine
transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated
that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in
the small intestine, but not hTHTR-1, transports metformin (<i>K</i><sub>m</sub> = 1.15 ± 0.2 mM) and other cationic compounds
(MPP<sup>+</sup> and famotidine). The uptake mechanism for hTHTR-2
was pH and electrochemical gradient sensitive. Furthermore, metformin
as well as other drugs including phenformin, chloroquine, verapamil,
famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both
thiamine and metformin. Species differences in the substrate specificity
of THTR-2 between human and mouse orthologues were observed. Taken
together, our data suggest that hTHTR-2 may play a role in the intestinal
absorption and tissue distribution of metformin and other organic
cations and that the transporter may be a target for drug–drug
and drug–nutrient interactions
Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3‑Kinase (PI3K) β Inhibitor
Atropisomerism is a type of axial
chirality in which enantiomers
or diastereoisomers arise due to hindered rotation around a bond axis.
In this manuscript, we report a case in which torsional scan studies
guided the thoughtful creation of a restricted axis of rotation between
two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β
inhibitor, generating a pair of atropisomeric compounds with significantly
different pharmacological and pharmacokinetic profiles. Emblematic
of these differences, the metabolism of inactive (<i>M</i>)-<b>28</b> is primarily due to the cytosolic enzyme aldehyde
oxidase, while active (<i>P</i>)-<b>28</b> has lower
affinity for aldehyde oxidase, resulting in substantially better metabolic
stability. Additionally, we report torsional scan and experimental
studies used to determine the barriers of rotation of this novel PI3Kβ
inhibitor
Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3‑Kinase (PI3K) β Inhibitor
Atropisomerism is a type of axial
chirality in which enantiomers
or diastereoisomers arise due to hindered rotation around a bond axis.
In this manuscript, we report a case in which torsional scan studies
guided the thoughtful creation of a restricted axis of rotation between
two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β
inhibitor, generating a pair of atropisomeric compounds with significantly
different pharmacological and pharmacokinetic profiles. Emblematic
of these differences, the metabolism of inactive (<i>M</i>)-<b>28</b> is primarily due to the cytosolic enzyme aldehyde
oxidase, while active (<i>P</i>)-<b>28</b> has lower
affinity for aldehyde oxidase, resulting in substantially better metabolic
stability. Additionally, we report torsional scan and experimental
studies used to determine the barriers of rotation of this novel PI3Kβ
inhibitor
Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3‑Kinase (PI3K) β Inhibitor
Atropisomerism is a type of axial
chirality in which enantiomers
or diastereoisomers arise due to hindered rotation around a bond axis.
In this manuscript, we report a case in which torsional scan studies
guided the thoughtful creation of a restricted axis of rotation between
two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β
inhibitor, generating a pair of atropisomeric compounds with significantly
different pharmacological and pharmacokinetic profiles. Emblematic
of these differences, the metabolism of inactive (<i>M</i>)-<b>28</b> is primarily due to the cytosolic enzyme aldehyde
oxidase, while active (<i>P</i>)-<b>28</b> has lower
affinity for aldehyde oxidase, resulting in substantially better metabolic
stability. Additionally, we report torsional scan and experimental
studies used to determine the barriers of rotation of this novel PI3Kβ
inhibitor
Discovery of a Phosphoinositide 3‑Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856
Phosphoinositide 3-kinase (PI3K)
β signaling is required to sustain cancer cell growth in which
the tumor suppressor phosphatase and tensin homolog (PTEN) has been
deactivated. This manuscript describes the discovery, optimization,
and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors
in which PI3Kβ potency was built in a PI3Kδ-selective
template. This work led to the discovery of a highly selective PI3Kβ/δ
inhibitor displaying excellent pharmacokinetic profile and efficacy
in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor
model
Discovery of Orally Efficacious Phosphoinositide 3‑Kinase δ Inhibitors with Improved Metabolic Stability
Aberrant signaling of phosphoinositide
3-kinase δ (PI3Kδ)
has been implicated in numerous pathologies including hematological
malignancies and rheumatoid arthritis. Described in this manuscript
are the discovery, optimization, and in vivo evaluation of a novel
series of pyridine-containing PI3Kδ inhibitors. This work led
to the discovery of <b>35</b>, a highly selective inhibitor
of PI3Kδ which displays an excellent pharmacokinetic profile
and is efficacious in a rodent model of rheumatoid arthritis