2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7376-80. doi: 10.1016/j.bmcl.2010.10.035. Epub 2010 Oct 15.

Abstract

A series of novel 2'-deoxy-2'-α-fluoro-2'-β-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / toxicity
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclic P-Oxides / chemistry*
  • Cyclic P-Oxides / pharmacokinetics
  • Cyclic P-Oxides / toxicity
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / toxicity
  • Hepacivirus / enzymology*
  • Humans
  • Molecular Conformation
  • Nucleosides / chemistry*
  • Nucleosides / pharmacokinetics
  • Nucleosides / toxicity
  • Nucleotides, Cyclic / chemical synthesis
  • Nucleotides, Cyclic / chemistry*
  • Nucleotides, Cyclic / toxicity
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Cyclic P-Oxides
  • Enzyme Inhibitors
  • Nucleosides
  • Nucleotides, Cyclic
  • PSI 352938
  • Prodrugs
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus