12 research outputs found
Rosiglitazone Induces Mitochondrial Biogenesis in Differentiated Murine 3T3-L1 and C3H/10T1/2 Adipocytes
Growing evidence indicates that PPARγ agonists, including rosiglitazone (RSG), induce adipose mitochondrial biogenesis. By systematically analyzing mitochondrial gene expression in two common murine adipocyte models, the current study aimed to further establish the direct role of RSG and capture temporal changes in gene transcription. Microarray profiling revealed that in fully differentiated 3T3-L1 and C3H/10T1/2 adipocytes treated with RSG or DMSO vehicle for 1, 2, 4, 7, 24, and 48 hrs, RSG overwhelmingly increased mitochondrial gene transcripts time dependently. The timing of the increases was consistent with the cascade of organelle biogenesis, that is, initiated by induction of transcription factor(s), followed by increases in the biosynthesis machinery, and then by increases in functional components. The transcriptional increases were further validated by increased mitochondrial staining, citrate synthase activity, and O2 consumption, and were found to be associated with increased adiponectin secretion. The work provided further insight on the mechanism of PPARγ-induced mitochondrial biogenesis in differentiated adipocytes
Preclinical Characterization of GSK2336805, a Novel Inhibitor of Hepatitis C Virus Replication That Selects for Resistance in NS5A
Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase
Imidazo[1,2-<i>a</i>]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization
A series of imidazo[1,2-<i>a</i>]pyridines
which directly
bind to HCV Non-Structural Protein 4B (NS4B) is described. This series
demonstrates potent <i>in vitro</i> inhibition of HCV replication
(EC<sub>50</sub> < 10 nM), direct binding to purified NS4B protein
(IC<sub>50</sub> < 20 nM), and an HCV resistance pattern associated
with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV
clinical assets, suggestive of the potential for additive or synergistic
combination with other small molecule inhibitors of HCV replication
Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants
The macrocyclic urea <b>2</b>, a byproduct in the
synthesis
of benzoxaborole <b>1</b>, was identified to be a novel and
potent HCV protease inhibitor. We further explored this motif by synthesizing
additional urea-based inhibitors and by characterizing them in replicase
HCV protease-resistant mutants assay. Several compounds, exemplified
by <b>12</b>, were found to be more potent in HCV replicon assays
than leading second generation inhibitors such as danoprevir and TMC-435350.
Additionally, following oral administration, inhibitor <b>12</b> was found in rat liver in significantly higher concentrations than
those reported for both danoprevir and TMC-435350, suggesting that
inhibitor <b>12</b> has the combination of anti-HCV and pharmacokinetic
properties that warrants further development of this series
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Novel macrocyclic HCV NS3 protease inhibitors derived from a-amino cyclic boronates
A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with a-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around a-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action