Novel oral anti-influenza prodrug candidate AV5075S
| Autor: | Ruben N. Karapetian, Natalia A. Shevkun, I. A. Leneva, I. T. Fedyakina, Oleg D. Mitkin, Olga O. Nevolina, Mark S. Veselov, Alexandre V. Ivachtchenko, Olga V. Mokrushina, Pavel M. Yamanushkin, Yan A. Ivanenkov, Vadim V. Bichko |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Microbiology (medical) Oseltamivir Pneumonia Viral Orthomyxoviridae Administration Oral Pharmacology Antiviral Agents Virus Rats Sprague-Dawley Mice chemistry.chemical_compound Dogs Orthomyxoviridae Infections Pharmacokinetics Animals Medicine Prodrugs Pharmacology (medical) biology business.industry Prodrug biology.organism_classification Virology Disease Models Animal Metabolic pathway Inhibitory potency Treatment Outcome Infectious Diseases chemistry biology.protein Administration Intravenous Female business Neuraminidase |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 69:1311-1324 |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dkt507 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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