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Статья
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 studywas 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. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Цитирование
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Версии
- 1. Version of Record от 2021-04-27
Метаданные
Название журнала
- Journal of Antimicrobial Chemotherapy
Том
- 69
Выпуск
- 5
Страницы
- 1311-1324
Ключевые слова
- 4 acetamido 5 amino 3 (1 ethylpropoxy) 1 cyclohexene 1 carboxylic acid; 4 amino 5 (2,2 difluoroacetamido) 3 (1 ethylpropoxy)cyclohex 1 enecarboxylic acid; antivirus agent; av 5027; av 5075s; av 5092; av 5095; av 5095s; av 5102; av5092; av5095; av5095s; laninamivir; mesylic acid derivative; oseltamivir; prodrug; sialidase; unclassified drug; zanamivir; [ 4 (2,2 difluoroacetylamino) 5 amino 3 (1 ethyl propoxy) cyclohex 1 enercarboxylic acid; [ 5 amino 4 (2,2 difluoroacetylamino) 3 (1 ethyl propoxy) cyclohex 1 enecarboxylic acid] ethyl ester mesylate; antivirus agent; prodrug; animal experiment; animal model; antiviral activity; article; beagle; controlled study; drug bioavailability; drug blood level; drug efficacy; drug metabolism; drug potency; drug stability; drug synthesis; female; human; IC 50; in vitro study; in vivo study; influenza; influenza A (H3N2); Influenza virus; male; molecular docking; mouse; nonhuman; pneumonia; quantitative structure activity relation; rat; single drug dose; therapy effect; virus infection; animal; disease model; dog; intravenous drug administration; oral drug administration; Orthomyxoviridae Infections; Pneumonia, Viral; Sprague Dawley rat; treatment outcome; virology; Administration, Intravenous; Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; Dogs; Female; Male; Mice; Orthomyxoviridae Infections; Pneumonia, Viral; Prodrugs; Rats, Sprague-Dawley; Treatment Outcome
Издатель
- Oxford University Press
Тип документа
- journal article
Источник
- scopus
