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

doi:10.1021/jm401492x

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

J Med Chem. 2014 Feb 13;57(3):759-69. doi: 10.1021/jm401492x. Epub 2014 Feb 3.

Authors

Dennis Schade¹, Joscha Kotthaus, Lukas Riebling, Jürke Kotthaus, Helge Müller-Fielitz, Walter Raasch, Oliver Koch, Nora Seidel, Michaela Schmidtke, Bernd Clement

Affiliation

¹ Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts University of Kiel , Gutenbergstrasse 76, 24118 Kiel, Germany.

PMID: 24422530
DOI: 10.1021/jm401492x

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Amidines / chemical synthesis*
Amidines / pharmacokinetics
Amidines / pharmacology
Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology
Biological Availability
Dogs
Drug Resistance, Viral*
Guanidines / chemical synthesis*
Guanidines / pharmacokinetics
Guanidines / pharmacology
Humans
Influenza A Virus, H1N1 Subtype / drug effects*
Influenza A Virus, H1N1 Subtype / genetics
Influenza A Virus, H3N2 Subtype / drug effects*
Madin Darby Canine Kidney Cells
Male
Molecular Docking Simulation
Mutation
Neuraminidase / antagonists & inhibitors
Neuraminidase / genetics
Oseltamivir / analogs & derivatives*
Oseltamivir / chemical synthesis*
Oseltamivir / pharmacokinetics
Oseltamivir / pharmacology
Prodrugs / chemical synthesis*
Prodrugs / pharmacokinetics
Prodrugs / pharmacology
Protein Binding
Rats
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Swine

Substances

Amidines
Antiviral Agents
Guanidines
Prodrugs
Oseltamivir
Neuraminidase