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

doi:10.1021/jm3008486

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 journal › Article › peer-review

49 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 language	English
Pages (from-to)	8657-8670
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	20
DOIs	https://doi.org/10.1021/jm3008486
Publication status	Published - Oct 25 2012
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Cheng, T. J. R., Weinheimer, S., Tarbet, E. B., Jan, J. T., Cheng, Y. S. E., Shie, J. J., Chen, C. L., Chen, C. A., Hsieh, W. C., Huang, P. W., Lin, W. H., Wang, S. Y., Fang, J. M., Hu, O. Y. P., & 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

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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.",

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

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AU - Lin, Wen Hao

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AU - Fang, Jim Min

AU - Hu, Oliver Yoa Pu

AU - Wong, Chi Huey

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Development of oseltamivir phosphonate congeners as anti-influenza agents

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