Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en

Takeshi Honda; Shuku Kubo; Takeshi Masuda; Masami Arai; Yoshiyuki Kobayashi; Makoto Yamashita

doi:10.1016/j.bmcl.2009.04.067

Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en

Bioorg Med Chem Lett. 2009 Jun 1;19(11):2938-40. doi: 10.1016/j.bmcl.2009.04.067. Epub 2009 Apr 20.

Authors

Takeshi Honda¹, Shuku Kubo, Takeshi Masuda, Masami Arai, Yoshiyuki Kobayashi, Makoto Yamashita

Affiliation

¹ Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co, Ltd, Tokyo, Japan. honda.takeshi.sx@daiichisankyo.co.jp

PMID: 19414262
DOI: 10.1016/j.bmcl.2009.04.067

Abstract

A series of ester prodrugs of 7-O-methyl derivative of Zanamivir (compound 3) was synthesized and their efficacy was evaluated in an influenza infected mice model by intranasal administration. Compound 7c (CS-8958), octanoyl ester prodrug of the C-9 alcohol of compound 3, was found to be much longer-acting than Zanamivir. Furthermore, the in vivo efficacies of compounds 12a, 12b, and 12c, the linear alkyl ester prodrug of the carboxylic acid, were comparable to that exerted by compound 7c.

MeSH terms

Administration, Intranasal
Alphainfluenzavirus / drug effects*
Alphainfluenzavirus / enzymology
Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Betainfluenzavirus / drug effects*
Betainfluenzavirus / enzymology
Esters
Mice
Neuraminidase / antagonists & inhibitors*
Neuraminidase / metabolism
Prodrugs / chemical synthesis*
Prodrugs / chemistry
Prodrugs / pharmacology
Zanamivir / pharmacology

Substances

Antiviral Agents
Esters
Prodrugs
Neuraminidase
Zanamivir