title: Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay.
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.
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: sarns@cdrd.ca.
authors.forename: Steve
authors.initials: S
authors.lastname: Arns
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Tan
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sun
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: Galey
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Zisman
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Fiona
authors.initials: F
authors.lastname: Ross
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Udechukwu
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Dercho
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Vionarica
authors.initials: V
authors.lastname: Gusti
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Paquette
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Murray
authors.initials: M
authors.lastname: Webb
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Elyse
authors.initials: E
authors.lastname: Bourque
authors.affiliation: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Withers
authors.affiliation: The Center for Drug Research and Development, 4th Floor-2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Liggins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D012794:Sialic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011355:Prodrugs; D012794:Sialic Acids; D014764:Viral Proteins; D009439:Neuraminidase
keywords: Bioavailability; Difluorosialic acid; Neuraminidase inhibitor; Prodrug; Snapshot PK screen