Discovery of a novel series of potent non-nucleoside inhibitors of hepatitis C virus NS5B

J Med Chem. 2013 Oct 24;56(20):8163-82. doi: 10.1021/jm401266k. Epub 2013 Oct 10.

Abstract

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 19.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Area Under Curve
  • Cell Line, Tumor
  • Dogs
  • Drug Discovery / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology
  • Hepacivirus / physiology
  • Hepatitis C / prevention & control
  • Hepatitis C / virology
  • Host-Pathogen Interactions / genetics
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy / methods
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridones / chemical synthesis
  • Pyridones / pharmacokinetics
  • Pyridones / pharmacology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Pyridones
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase

Associated data

  • PDB/4MK7
  • PDB/4MK8
  • PDB/4MK9
  • PDB/4MKA
  • PDB/4MKB