title: Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts University of Kiel , Gutenbergstrasse 76, 24118 Kiel, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
authors.forename: Joscha
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Lukas
authors.initials: L
authors.lastname: Riebling
authors.forename: Jürke
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Helge
authors.initials: H
authors.lastname: Müller-Fielitz
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
authors.forename: Nora
authors.initials: N
authors.lastname: Seidel
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D024882:Drug Resistance, Viral; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D062105:Molecular Docking Simulation; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000578:Amidines; D000998:Antiviral Agents; D006146:Guanidines; D011355:Prodrugs; D053139:Oseltamivir; D009439:Neuraminidase