Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay

Bioorg Med Chem Lett. 2015 Jun 15;25(12):2505-9. doi: 10.1016/j.bmcl.2015.04.059. Epub 2015 Apr 24.

Abstract

Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.

Keywords: Bioavailability; Difluorosialic acid; Neuraminidase inhibitor; Prodrug; Snapshot PK screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Half-Life
  • Mice
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / metabolism
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Sialic Acids / chemical synthesis
  • Sialic Acids / chemistry*
  • Sialic Acids / pharmacokinetics
  • Viral Proteins / antagonists & inhibitors*
  • Viral Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Prodrugs
  • Sialic Acids
  • Viral Proteins
  • Neuraminidase