2 research outputs found
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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Synthesis and evaluation of novel a-amino cyclic boronates as inhibitors of HCV NS3 protease
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described