Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)

J Med Chem. 2018 May 10;61(9):4052-4066. doi: 10.1021/acs.jmedchem.8b00082. Epub 2018 Apr 23.

Abstract

Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Drug Design*
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Mice
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship
  • Tissue Distribution
  • Virus Replication / drug effects

Substances

  • ABT-530
  • Antiviral Agents
  • Benzimidazoles
  • Pyrrolidines