Abstract
Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / pharmacokinetics
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Acetamides / pharmacology
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Administration, Oral
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Alphainfluenzavirus / drug effects*
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Alphainfluenzavirus / enzymology
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Alphainfluenzavirus / genetics
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Betainfluenzavirus / drug effects*
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Betainfluenzavirus / enzymology
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Biological Availability
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Blood Proteins / metabolism
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Cyclohexenes / chemical synthesis*
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Cyclohexenes / pharmacokinetics
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Cyclohexenes / pharmacology
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Cytopathogenic Effect, Viral / drug effects
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Dogs
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Drug Resistance, Viral
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Drug Stability
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Female
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Humans
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Influenza A Virus, H1N1 Subtype / drug effects
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Influenza A Virus, H1N1 Subtype / enzymology
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Influenza A Virus, H1N1 Subtype / genetics
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Influenza A Virus, H5N1 Subtype / drug effects
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Influenza A Virus, H5N1 Subtype / enzymology
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Madin Darby Canine Kidney Cells
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Male
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Mutation
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Neuraminidase / antagonists & inhibitors*
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Orthomyxoviridae Infections / drug therapy
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Oseltamivir / pharmacology
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Phosphorous Acids
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Protein Binding
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Rats
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Structure-Activity Relationship
Substances
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Acetamides
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Antiviral Agents
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Blood Proteins
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Cyclohexenes
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Phosphorous Acids
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tamiphosphor
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Oseltamivir
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Neuraminidase