Discovery of novel pan-genotypic HCV NS5A inhibitors containing a novel tetracyclic core

Bioorg Med Chem Lett. 2019 Mar 1;29(5):700-706. doi: 10.1016/j.bmcl.2019.01.031. Epub 2019 Jan 25.

Abstract

A series of novel tetracyclic core-containing HCV NS5A inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.

Keywords: HCV; NS5A inhibitor; Pan-genotype; THP; Tetracycle; Tetrahydro-2H-pyran.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Drug Discovery*
  • Genotype*
  • Half-Life
  • Hepacivirus / drug effects*
  • Rats
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus