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

研究成果: 雜誌貢獻文章同行評審

46 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)8657-8670
頁數14
期刊Journal of Medicinal Chemistry
55
發行號20
DOIs
出版狀態已發佈 - 10月 25 2012
對外發佈

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

指紋

深入研究「Development of oseltamivir phosphonate congeners as anti-influenza agents」主題。共同形成了獨特的指紋。

引用此