title: Development of oseltamivir phosphonate congeners as anti-influenza agents.
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.
authors.affiliation: The Genomics Research Center,  Academia Sinica , No. 128, Sec. 2, Academia Road, Taipei 11529, Taiwan.
authors.forename: Ting-Jen R
authors.initials: TJ
authors.lastname: Cheng
authors.forename: Steven
authors.initials: S
authors.lastname: Weinheimer
authors.forename: E Bart
authors.initials: EB
authors.lastname: Tarbet
authors.forename: Jia-Tsrong
authors.initials: JT
authors.lastname: Jan
authors.forename: Yih-Shyun E
authors.initials: YS
authors.lastname: Cheng
authors.forename: Jiun-Jie
authors.initials: JJ
authors.lastname: Shie
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: Chih-An
authors.initials: CA
authors.lastname: Chen
authors.forename: Wei-Che
authors.initials: WC
authors.lastname: Hsieh
authors.forename: Pei-Wei
authors.initials: PW
authors.lastname: Huang
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Lin
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Wang
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.forename: Oliver Yoa-Pu
authors.initials: OY
authors.lastname: Hu
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D053138:Cyclohexenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004285:Dogs; D024882:Drug Resistance, Viral; D004355:Drug Stability; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology; D029521:Alphainfluenzavirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029524:Betainfluenzavirus / Q000187:drug effects* / Q000201:enzymology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D053139:Oseltamivir / Q000494:pharmacology / Q000031:analogs & derivatives; D010757:Phosphorous Acids; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D001798:Blood Proteins; D053138:Cyclohexenes; D010757:Phosphorous Acids; C530824:tamiphosphor; D053139:Oseltamivir; D009439:Neuraminidase