Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 2: Variation of the 2- and 6-pyridazinone substituents

Bioorg Med Chem Lett. 2008 Feb 15;18(4):1419-24. doi: 10.1016/j.bmcl.2008.01.005. Epub 2008 Jan 8.

Abstract

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure-activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described.

MeSH terms

  • Crystallography, X-Ray
  • Drug Design
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • RNA-Dependent RNA Polymerase / metabolism
  • Thiadiazines / chemical synthesis
  • Thiadiazines / chemistry
  • Thiadiazines / pharmacology
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Pyridazines
  • Thiadiazines
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase