4 research outputs found
Morphology and Proton Transport in Humidified Phosphonated Peptoid Block Copolymers
Polymers
that conduct protons in the hydrated state are of crucial
importance in a wide variety of clean energy applications such as
hydrogen fuel cells and artificial photosynthesis. Phosphonated and
sulfonated polymers are known to conduct protons at low water content.
In this paper, we report on the synthesis phosphonated peptoid diblock
copolymers, poly-<i>N</i>-(2-ethyl)ÂhexylÂglycine-<i>block</i>-poly-<i>N</i>-phosphonoÂmethylÂglycine
(pNeh-<i>b</i>-pNpm), with volume fractions of pNpm (Ï<sub>Npm</sub>) values ranging from 0.13 to 0.44 and dispersity (<i>Ä</i>) †1.0003. The morphologies of the dry block
copolypeptoids were determined by transmission electron microscopy
and in both the dry and hydrated states by synchrotron small-angle
X-ray scattering. Dry samples with Ï<sub>Npm</sub> > 0.13
exhibited
a lamellar morphology. Upon hydration, the lowest molecular weight
sample transitioned to a hexagonally packed cylinder morphology, while
the others maintained their dry morphologies. Water uptake of all
of the ordered samples was 8.1 ± 1.1 water molecules per phosphonate
group. In spite of this, the proton conductivity of the ordered pNeh-<i>b</i>-pNpm copolymers ranged from 0.002 to 0.008 S/cm. We demonstrate
that proton conductivity is maximized in high molecular weight, symmetric
pNeh-<i>b</i>-pNpm copolymers
Piperazine Oxadiazole Inhibitors of Acetyl-CoA Carboxylase
Acetyl-CoA
carboxylase (ACC) is a target of interest for the treatment
of metabolic syndrome. Starting from a biphenyloxadiazole screening
hit, a series of piperazine oxadiazole ACC inhibitors was developed.
Initial pharmacokinetic liabilities of the piperazine oxadiazoles
were overcome by blocking predicted sites of metabolism, resulting
in compounds with suitable properties for further in vivo studies.
Compound <b>26</b> was shown to inhibit malonyl-CoA production
in an in vivo pharmacodynamic assay and was advanced to a long-term
efficacy study. Prolonged dosing with compound <b>26</b> resulted
in impaired glucose tolerance in diet-induced obese (DIO) C57BL6 mice,
an unexpected finding
Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series
As part of our effort toward developing an effective
therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class
II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)Âoxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified.
Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2
proteins led to a novel strategy for designing more selective analogues
of <b>1</b>. Along with detailed SAR information, we demonstrate
that the low kinase selectivity associated with class II c-Met inhibitors
can be improved significantly. This work resulted in the discovery
of potent c-Met inhibitors with improved selectivity profiles over
VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship
between kinase selectivity and in vivo efficacy in tumor xenograft
models. Compound <b>59e</b> (AMG 458) was ultimately advanced
into preclinical safety studies
Small Molecule Disruptors of the GlucokinaseâGlucokinase Regulatory Protein Interaction: 3. StructureâActivity Relationships within the Aryl Carbinol Region of the <i>N</i>âArylsulfonamidoâ<i>N</i>âČâarylpiperazine Series
We have recently reported a novel
approach to increase cytosolic
glucokinase (GK) levels through the binding of a small molecule to
its endogenous inhibitor, glucokinase regulatory protein (GKRP). These
initial investigations culminated in the identification of 2-(4-((2<i>S</i>)-4-((6-amino-3-pyridinyl)Âsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)Âphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol
(<b>1</b>, AMG-3969), a compound that effectively enhanced GK
translocation and reduced blood glucose levels in diabetic animals.
Herein we report the results of our expanded SAR investigations that
focused on modifications to the aryl carbinol group of this series.
Guided by the X-ray cocrystal structure of compound <b>1</b> bound to hGKRP, we identified several potent GKâGKRP disruptors
bearing a diverse set of functionalities in the aryl carbinol region.
Among them, sulfoximine and pyridinyl derivatives <b>24</b> and <b>29</b> possessed excellent potency as well as favorable PK properties.
When dosed orally in <i>db</i>/<i>db</i> mice,
both compounds significantly lowered fed blood glucose levels (up
to 58%)