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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8657-8670
Number of pages14
JournalJournal of Medicinal Chemistry
Volume55
Issue number20
DOIs
Publication statusPublished - Oct 25 2012
Externally publishedYes

Fingerprint

Oseltamivir
Organophosphonates
Human Influenza
Orthomyxoviridae
Esters
Neuraminidase
Liver Microsomes
Therapeutic Uses
Intravenous Administration
Biological Availability
Oral Administration
Blood Proteins
Stomach
Pharmacokinetics
Dogs
Infection
tamiphosphor

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Cheng, T. J. R., Weinheimer, S., Tarbet, E. B., Jan, J. T., Cheng, Y. S. E., Shie, J. J., ... Wong, C. H. (2012). Development of oseltamivir phosphonate congeners as anti-influenza agents. Journal of Medicinal Chemistry, 55(20), 8657-8670. https://doi.org/10.1021/jm3008486

Development of oseltamivir phosphonate congeners as anti-influenza agents. / Cheng, Ting Jen R; Weinheimer, Steven; Tarbet, E. Bart; Jan, Jia Tsrong; Cheng, Yih Shyun E; Shie, Jiun Jie; Chen, Chun Lin; Chen, Chih An; Hsieh, Wei Che; Huang, Pei Wei; Lin, Wen Hao; Wang, Shi Yun; Fang, Jim Min; Hu, Oliver Yoa Pu; Wong, Chi Huey.

In: Journal of Medicinal Chemistry, Vol. 55, No. 20, 25.10.2012, p. 8657-8670.

Research output: Contribution to journalArticle

Cheng, TJR, Weinheimer, S, Tarbet, EB, Jan, JT, Cheng, YSE, Shie, JJ, Chen, CL, Chen, CA, Hsieh, WC, Huang, PW, Lin, WH, Wang, SY, Fang, JM, Hu, OYP & Wong, CH 2012, 'Development of oseltamivir phosphonate congeners as anti-influenza agents', Journal of Medicinal Chemistry, vol. 55, no. 20, pp. 8657-8670. https://doi.org/10.1021/jm3008486
Cheng TJR, Weinheimer S, Tarbet EB, Jan JT, Cheng YSE, Shie JJ et al. Development of oseltamivir phosphonate congeners as anti-influenza agents. Journal of Medicinal Chemistry. 2012 Oct 25;55(20):8657-8670. https://doi.org/10.1021/jm3008486
Cheng, Ting Jen R ; Weinheimer, Steven ; Tarbet, E. Bart ; Jan, Jia Tsrong ; Cheng, Yih Shyun E ; Shie, Jiun Jie ; Chen, Chun Lin ; Chen, Chih An ; Hsieh, Wei Che ; Huang, Pei Wei ; Lin, Wen Hao ; Wang, Shi Yun ; Fang, Jim Min ; Hu, Oliver Yoa Pu ; Wong, Chi Huey. / Development of oseltamivir phosphonate congeners as anti-influenza agents. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 20. pp. 8657-8670.
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