TY - JOUR
T1 - Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A
AU - Schade, Dennis
AU - Kotthaus, Joscha
AU - Riebling, Lukas
AU - Kotthaus, Jürke
AU - Müller-Fielitz, Helge
AU - Raasch, Walter
AU - Koch, Oliver
AU - Seidel, Nora
AU - Schmidtke, Michaela
AU - Clement, Bernd
PY - 2014/2/13
Y1 - 2014/2/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84894094139&partnerID=8YFLogxK
U2 - 10.1021/jm401492x
DO - 10.1021/jm401492x
M3 - Journal articles
C2 - 24422530
AN - SCOPUS:84894094139
VL - 57
SP - 759
EP - 769
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 3
ER -