1 research outputs found
Discovery of a Novel Series of Potent Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B
Hepatitis
C virus (HCV) is a major global public health problem. While the current
standard of care, a direct-acting antiviral (DAA) protease inhibitor
taken in combination with pegylated interferon and ribavirin, represents
a major advancement in recent years, an unmet medical need still exists
for treatment modalities that improve upon both efficacy and tolerability.
Toward those ends, much effort has continued to focus on the discovery
of new DAAs, with the ultimate goal to provide interferon-free combinations.
The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA
therapeutic target for inhibition that has attracted much interest
over the past decade. Herein, we report the discovery and optimization
of a novel series of inhibitors of HCV NS5B, through the use of structure-based
design applied to a fragment-derived starting point. Issues of potency,
pharmacokinetics, and early safety were addressed in order to provide
a clinical candidate in fluoropyridone <b>19</b>