Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7207-13. doi: 10.1016/j.bmcl.2012.09.061. Epub 2012 Oct 2.

Abstract

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.

MeSH terms

  • Animals
  • Binding Sites
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Catalytic Domain
  • Cyclization
  • Genotype
  • Half-Life
  • Hepacivirus / enzymology*
  • Hepacivirus / genetics
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Liver / metabolism
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / pharmacokinetics
  • Molecular Docking Simulation
  • Mutation
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Macrocyclic Compounds
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Protease Inhibitors
  • Viral Nonstructural Proteins