Novel oral anti-influenza drug candidate AV5080
| Autor: | Mark S. Veselov, Natalia A. Shevkun, Ruben N. Karapetian, Alexandre V. Ivachtchenko, Vadim V. Bichko, Oleg D. Mitkin, Pavel M. Yamanushkin, I. A. Leneva, Yan A. Ivanenkov, Olga V. Borisova |
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| Rok vydání: | 2014 |
| Předmět: |
Microbiology (medical)
Oseltamivir Orthomyxoviridae Administration Oral Neuraminidase Pharmacology medicine.disease_cause Antiviral Agents chemistry.chemical_compound Inhibitory Concentration 50 Viral Proteins Dogs Influenza A Virus H1N1 Subtype Pharmacokinetics In vivo Medicine Potency Animals Pharmacology (medical) Enzyme Inhibitors biology Influenza A Virus H5N1 Subtype business.industry virus diseases biology.organism_classification Virology Influenza A virus subtype H5N1 Rats Molecular Docking Simulation Infectious Diseases chemistry biology.protein Female Pharmacophore business |
| Zdroj: | The Journal of antimicrobial chemotherapy. 69(7) |
| ISSN: | 1460-2091 |
| Popis: | Objectives 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. |
| Databáze: | OpenAIRE |
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