Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors

Bioorg Med Chem Lett. 2015 May 1;25(9):1990-4. doi: 10.1016/j.bmcl.2015.03.013. Epub 2015 Mar 14.

Abstract

VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.

Keywords: Influenza; Isostere; VX-787.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Carboxylic Acids / chemistry
  • Dose-Response Relationship, Drug
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Influenza A virus / drug effects*
  • Influenza A virus / enzymology
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Structure-Activity Relationship
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Antiviral Agents
  • Aza Compounds
  • Carboxylic Acids
  • Indoles
  • PB2 protein, influenza virus
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Viral Proteins
  • pimodivir