Development of oseltamivir phosphonate congeners as anti-influenza agents

Ting Jen R Cheng, Steven Weinheimer, E. Bart Tarbet, Jia Tsrong Jan, Yih Shyun E Cheng, Jiun Jie Shie, Chun Lin Chen, Chih An Chen, Wei Che Hsieh, Pei Wei Huang, Wen Hao Lin, Shi Yun Wang, Jim Min Fang, Oliver Yoa Pu Hu, Chi Huey Wong

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46 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)8657-8670
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number20
Publication statusPublished - Oct 25 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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