title: Novel oral anti-influenza drug candidate AV5080.
abstract: OBJECTIVE
  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.
authors.affiliation: ASAVI LLC, Hallandale Beach, FL, USA Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia ChemDiv, San Diego, CA, USA av@asavillc.com.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia ChemDiv, San Diego, CA, USA The Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Reg., Russia.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia.
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia.
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Yamanushkin
authors.affiliation: ChemDiv, San Diego, CA, USA.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Bichko
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Shevkun
authors.affiliation: Chemical Diversity Research Institute, Khimki, Moscow Reg., Russia.
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Karapetian
authors.affiliation: I. Mechnikov Research Institute of Vaccines and Sera of Russian Academy of Medical Science, Moscow, Russia.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Leneva
authors.affiliation: I. Mechnikov Research Institute of Vaccines and Sera of Russian Academy of Medical Science, Moscow, Russia.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Borisova
authors.affiliation: The Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Reg., Russia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Veselov
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000302:isolation & purification* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D051381:Rats; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; C487630:NA protein, influenza A virus; D009439:Neuraminidase
keywords: antiviral; neuraminidase inhibitors; pharmacokinetics