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 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments

Bioorg Med Chem Lett. 2008 Jun 1;18(11):3446-55. doi: 10.1016/j.bmcl.2008.02.072. Epub 2008 Mar 5.

Abstract

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / blood
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics*
  • Combinatorial Chemistry Techniques
  • Drug Design
  • Hepacivirus / drug effects*
  • Humans
  • Microsomes, Liver / drug effects
  • Molecular Structure
  • Pyridazines / blood
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacokinetics*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • Pyridazines
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase