2 research outputs found
De Novo Fragment Design: A Medicinal Chemistry Approach to Fragment-Based Lead Generation
The use of fragments with low binding
affinity for their targets
as starting points has received much attention recently. Screening
of fragment libraries has been the most common method to find attractive
starting points. Herein, we describe a unique, alternative approach
to generating fragment leads. A binding model was developed and a
set of guidelines were then selected to use this model to design fragments,
enabling our discovery of a novel fragment with high LE
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>