title: Novel oral anti-influenza prodrug candidate AV5075S.
abstract: OBJECTIVE
  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.
authors.affiliation: ASAVI LLC, Hallandale Beach, FL 33009, USA.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.forename: Oleg D
authors.initials: OD
authors.lastname: Mitkin
authors.forename: Pavel M
authors.initials: PM
authors.lastname: Yamanushkin
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Bichko
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Shevkun
authors.forename: Olga V
authors.initials: OV
authors.lastname: Mokrushina
authors.forename: Olga O
authors.initials: OO
authors.lastname: Nevolina
authors.forename: Ruben N
authors.initials: RN
authors.lastname: Karapetian
authors.forename: Irina A
authors.initials: IA
authors.lastname: Leneva
authors.forename: Irina T
authors.initials: IT
authors.lastname: Fedyakina
authors.forename: Mark S
authors.initials: MS
authors.lastname: Veselov
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D008297:Male; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D011024:Pneumonia, Viral / Q000188:drug therapy / Q000821:virology; D011355:Prodrugs / Q000008:administration & dosage*; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs
keywords: AV5027; AV5075; antiviral; neuraminidase inhibitors; pharmacokinetics