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J Antimicrob Chemother. 2014 Jan 15. [Epub ahead of print]
Novel oral anti-influenza prodrug candidate AV5075S.
Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Yamanushkin PM, Bichko VV, Shevkun NA, Mokrushina OV, Nevolina OO, Karapetian RN, Leneva IA, Fedyakina IT, Veselov MS.
Author information
Abstract
OBJECTIVES:
Development of a novel drug candidate with improved activity against influenza virus neuraminidase (NA) compared with currently available therapeutics.
METHODS:
Synthesized compounds were evaluated in vitro and in vivo. Three-dimensional molecular docking was successfully applied to classify compounds within the series by inhibitory potency. Stability was investigated in blood samples and in animal models. A pharmacokinetic study was performed in dogs and rats using peroral and intravenous administration.
RESULTS:
A novel highly potent drug candidate [(3R,4R,5S)-4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid; AV5027] and its prodrug ethyl ester (AV5075S) were synthesized and tested. AV5027 and AV5075S exhibit picomolar activity against influenza virus NA. AV5075S inhibited NA in a model of pneumonia using mouse-adapted A/Aichi/2/68 (H3N2) virus significantly more strongly than oseltamivir phosphate. A general metabolic pathway was constructed for the parent compound based on experimental results and theoretical analyses.
CONCLUSIONS:
AV5075S can be reasonably regarded as a novel 'next in class' oral drug candidate for the treatment of influenza.
KEYWORDS:
AV5027, AV5075, antiviral, neuraminidase inhibitors, pharmacokinetics
PMID:
24428978
[PubMed - as supplied by publisher]
Novel oral anti-influenza prodrug candidate AV5075S.
Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Yamanushkin PM, Bichko VV, Shevkun NA, Mokrushina OV, Nevolina OO, Karapetian RN, Leneva IA, Fedyakina IT, Veselov MS.
Author information
Abstract
OBJECTIVES:
Development of a novel drug candidate with improved activity against influenza virus neuraminidase (NA) compared with currently available therapeutics.
METHODS:
Synthesized compounds were evaluated in vitro and in vivo. Three-dimensional molecular docking was successfully applied to classify compounds within the series by inhibitory potency. Stability was investigated in blood samples and in animal models. A pharmacokinetic study was performed in dogs and rats using peroral and intravenous administration.
RESULTS:
A novel highly potent drug candidate [(3R,4R,5S)-4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylic acid; AV5027] and its prodrug ethyl ester (AV5075S) were synthesized and tested. AV5027 and AV5075S exhibit picomolar activity against influenza virus NA. AV5075S inhibited NA in a model of pneumonia using mouse-adapted A/Aichi/2/68 (H3N2) virus significantly more strongly than oseltamivir phosphate. A general metabolic pathway was constructed for the parent compound based on experimental results and theoretical analyses.
CONCLUSIONS:
AV5075S can be reasonably regarded as a novel 'next in class' oral drug candidate for the treatment of influenza.
KEYWORDS:
AV5027, AV5075, antiviral, neuraminidase inhibitors, pharmacokinetics
PMID:
24428978
[PubMed - as supplied by publisher]
