Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4181-5. doi: 10.1016/j.bmcl.2008.05.083. Epub 2008 May 24.

Abstract

A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacokinetics*
  • Chemistry, Pharmaceutical / methods
  • Crystallography, X-Ray / methods
  • Drug Design
  • Enzyme Inhibitors / pharmacokinetics*
  • Genotype
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Conformation
  • RNA, Viral / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacokinetics
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • RNA, Viral
  • Thiazoles
  • Thiophenes
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus