tetano
Editor, Senior Moderator
J Med Chem. 2014 Jan 14. [Epub ahead of print]
Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
Schade D, Kotthaus J, Riebling L, Kotthaus J, M?ller-Fielitz H, Raasch W, Koch O, Seidel N, Schmidtke M, Clement B.
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 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.
PMID:
24422530
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24422530
Development of novel potent orally bioavailable oseltamivir derivatives active against resistant influenza A.
Schade D, Kotthaus J, Riebling L, Kotthaus J, M?ller-Fielitz H, Raasch W, Koch O, Seidel N, Schmidtke M, Clement B.
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 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.
PMID:
24422530
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24422530