Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A

Dennis Schade*, Joscha Kotthaus, Lukas Riebling, Jürke Kotthaus, Helge Müller-Fielitz, Walter Raasch, Oliver Koch, Nora Seidel, Michaela Schmidtke, Bernd Clement

*Korrespondierende/r Autor/-in für diese Arbeit
34 Zitate (Scopus)

Abstract

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 - in the form of its N-hydroxy prodrug - successfully tackled the two key limitations of currently used NA inhibitors, as exemplified with oseltamivir.

OriginalspracheEnglisch
ZeitschriftJournal of Medicinal Chemistry
Jahrgang57
Ausgabenummer3
Seiten (von - bis)759-769
Seitenumfang11
ISSN0022-2623
DOIs
PublikationsstatusVeröffentlicht - 13.02.2014

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