8 research outputs found
Supplemental Material, activL_5-year_Meta-analysis_Manuscript-Supplemental-Mar_9_2017 - Comparison of Lumbar Total Disc Replacement With Surgical Spinal Fusion for the Treatment of Single-Level Degenerative Disc Disease: A Meta-Analysis of 5-Year Outcomes From Randomized Controlled Trials
<p>Supplemental Material, activL_5-year_Meta-analysis_Manuscript-Supplemental-Mar_9_2017 for Comparison of Lumbar Total Disc Replacement With Surgical Spinal Fusion for the Treatment of Single-Level Degenerative Disc Disease: A Meta-Analysis of 5-Year Outcomes From Randomized Controlled Trials by Jack Zigler, Matthew F. Gornet, Nicole Ferko, Chris Cameron, Francine W. Schranck, and Leena Patel in Global Spine Journal</p
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
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 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
2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors
Inhibition of phosphoinositide 3-kinase
δ (PI3Kδ) is
an appealing target for several hematological malignancies and inflammatory
diseases. Herein, we describe the discovery and optimization of a
series of propeller shaped PI3Kδ inhibitors comprising a novel
triaminopyrimidine hinge binder. Combinations of electronic and structural
strategies were employed to mitigate aldehyde oxidase mediated metabolism.
This medicinal chemistry effort culminated in the identification of <b>52</b>, a potent and highly selective inhibitor of PI3Kδ
that demonstrates efficacy in a rat model of arthritis
2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors
Inhibition of phosphoinositide 3-kinase
δ (PI3Kδ) is
an appealing target for several hematological malignancies and inflammatory
diseases. Herein, we describe the discovery and optimization of a
series of propeller shaped PI3Kδ inhibitors comprising a novel
triaminopyrimidine hinge binder. Combinations of electronic and structural
strategies were employed to mitigate aldehyde oxidase mediated metabolism.
This medicinal chemistry effort culminated in the identification of <b>52</b>, a potent and highly selective inhibitor of PI3Kδ
that demonstrates efficacy in a rat model of arthritis