Novel oral anti-influenza prodrug candidate AV5075S
Alexandre V Ivachtchenko1, Yan A Ivanenkov, Oleg D Mitkin
1ASAVI LLC, Hallandale Beach, FL 33009, USA.
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.
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