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J Antimicrob Chemother. 2014 Jul;69(7):1892-902. doi: 10.1093/jac/dku074. Epub 2014 Apr 11.

Novel oral anti-influenza drug candidate AV5080.

Author information

1
ASAVI LLC, Hallandale Beach, FL, USA Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia ChemDiv, San Diego, CA, USA av@asavillc.com.
2
Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia ChemDiv, San Diego, CA, USA The Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Reg., Russia.
3
Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia.
4
ChemDiv, San Diego, CA, USA.
5
I. Mechnikov Research Institute of Vaccines and Sera of Russian Academy of Medical Science, Moscow, Russia.
6
The Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Reg., Russia.

Abstract

OBJECTIVES:

Development of a novel drug candidate with improved potency against influenza virus neuraminidase compared with currently available therapeutics, and high activity against oseltamivir-resistant viruses.

METHODS:

A number of synthetic compounds were evaluated for antiviral properties in vitro and in vivo. Three-dimensional molecular docking, assisted by a pharmacophore model, was applied to classify compounds within the series by their inhibitory potency. Compound stability in blood and in animal models was determined. Pharmacokinetic studies in dogs and rats after oral or intravenous administration were performed.

RESULTS:

A novel highly potent drug candidate [(3R,4R,5S)-5-[(diaminomethylene)amino]-3-(1-ethylpropoxy)-4-[(fluoroacetyl)amino]cyclohex-1-ene-1-carboxylic acid; AV5080] was synthesized and tested. AV5080 exhibited high activity against influenza virus neuraminidase in vitro, with IC(50) values of 0.03 nM and 0.07 nM against the neuraminidase of A/Duck/Minnesota/1525/1981/H5N1 and A/Perth/265/2009/H1N1 (wild-type), respectively. Notably, AV5080 was highly active against oseltamivir-resistant influenza viruses.

CONCLUSIONS:

Based on the results presented in this study, AV5080 is a promising novel oral drug candidate for the treatment of influenza, including oseltamivir-resistant types. Further pre-clinical development of AV5080 is warranted.

KEYWORDS:

antiviral; neuraminidase inhibitors; pharmacokinetics

PMID:
24729605
DOI:
10.1093/jac/dku074
[Indexed for MEDLINE]

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