Multi-step parallel synthesis enabled optimization of benzofuran derivatives as pan-genotypic non-nucleoside inhibitors of HCV NS5B

Bioorg Med Chem Lett. 2020 Apr 1;30(7):127004. doi: 10.1016/j.bmcl.2020.127004. Epub 2020 Feb 4.

Abstract

In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with <10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties.

Keywords: Lead optimization; Multi-step parallel libraries; NS5B NNI inhibitors; Pan-genotypic potency.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Benzofurans / chemical synthesis
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / enzymology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Rats, Wistar
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Benzofurans
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus