Development of Novel Potent Orally Bioavailable Oseltamivir Derivatives Active against Resistant Influenza A

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• 作者：Dennis Schade ; Joscha Kotthaus ; Lukas Riebling ; Jürke Kotthaus ; Helge Müller-Fielitz ; Walter Raasch ; Oliver Koch ; Nora Seidel ; Michaela Schmidtke ; Bernd Clement
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：759-769
• 全文大小：511K
• ISSN：1520-4804

文摘

With the emergence of oseltamivir-resistant influenza viruses and in view of a highly pathogenic flu pandemic, it is important to develop new anti-influenza agents. Here, the development of neuraminidase (NA) inhibitors that were designed to overcome resistance mechanisms along with unfavorable pharmacokinetic (PK) properties is described. Several 5-guanidino- and 5-amidino-based oseltamivir derivatives were synthesized and profiled for their anti-influenza activity and in vitro and in vivo PK properties. Amidine 6 and guanidine 7 were comparably effective against a panel of different A/H1N1 and A/H3N2 strains and also inhibited mutant A/H1N1 neuraminidase. Among different prodrug strategies pursued, a simple amidoxime ethyl ester (9) exhibited a superior PK profile with an oral bioavailability of 31% (rats), which is comparable to oseltamivir (36%). Thus, bioisosteric replacement of the 5-guanidine with an acetamidine鈥攊n the form of its N-hydroxy prodrug鈥攕uccessfully tackled the two key limitations of currently used NA inhibitors, as exemplified with oseltamivir.