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

[Display omitted] 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 f...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-06, Vol.25 (12), p.2505-2509
Main Authors: Arns, Steve, Tan, Jason, Sun, Sharon, Galey, Adam, Zisman, Natalia, Ross, Fiona, Udechukwu, Jenna, Dercho, Samantha, Gusti, Vionarica, Paquette, Jay, Webb, Murray, Bourque, Elyse, Withers, Stephen G., Liggins, Richard
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Bioavailability
Biological Availability
Difluorosialic acid
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacokinetics
Half-Life
Mice
Neuraminidase - antagonists & inhibitors
Neuraminidase - metabolism
Neuraminidase inhibitor
Prodrug
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Sialic Acids - chemical synthesis
Sialic Acids - chemistry
Sialic Acids - pharmacokinetics
Snapshot PK screen
Viral Proteins - antagonists & inhibitors
Viral Proteins - metabolism
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.04.059