Novel oral anti-influenza prodrug candidate AV5075S

Received 12 August 2013; returned 21 September 2013; revised 14 November 2013; accepted 4 December 2013Objectives:Developmentofanoveldrugcandidatewithimprovedactivityagainstinfluenzavirusneuraminidase(NA) compared with currently available therapeutics.Methods:Synthesizedcompoundswereevaluatedinvitroandinvivo.Three-dimensionalmoleculardockingwassuccessfully applied to classify compounds within the series by inhibitory potency. Stability was investigated inbloodsamplesandinanimalmodels.Apharmacokineticstudywasperformedindogsandratsusingperoralandintravenous administration.Results: A novel highly potent drug candidate [(3R,4R,5S)-4-(2,2-difluoroacetylamino)-5-amino-3-(1-ethyl-pro-poxy)-cyclohex-1-enecarboxylic acid; AV5027] and its prodrug ethyl ester (AV5075S) were synthesized andtested. AV5027 and AV5075S exhibit picomolar activity against influenza virus NA. AV5075S inhibited NA in amodel of pneumonia using mouse-adapted A/Aichi/2/68 (H3N2) virus significantly morestrongly thanoseltami-vir phosphate. A general metabolic pathway was constructed for the parent compound based on experimentalresults and theoretical analyses.Conclusions:AV5075Scanbereasonablyregardedasanovel‘nextinclass’oraldrugcandidateforthetreatmentof influenza.Keywords: AV5075, AV5027, antiviral, neuraminidase inhibitors, pharmacokinetics