Discovery of a β-d -2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus
| العنوان: | Discovery of a β- |
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| المؤلفون: | Jinfa Du, Angela M. Lam, Shalini Bansal, Rachakonda Suguna, Congrong Niu, Meg Keilman, Michael J. Otto, Donghui Bao, Bruce S. Ross, Peiyuan Wang, Dhanapalan Nagarathnam, Wonsuk Chang, Holly M. Micolochick Steuer, Michael J. Sofia, Hai-Ren Zhang, Phillip A. Furman, P. Ganapati Reddy, Christine Espiritu |
| المصدر: | Journal of Medicinal Chemistry. 53:7202-7218 |
| بيانات النشر: | American Chemical Society (ACS), 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Hepatitis C virus, Protide, Hepacivirus, In Vitro Techniques, Viral Nonstructural Proteins, Crystallography, X-Ray, medicine.disease_cause, Antiviral Agents, Cell Line, Structure-Activity Relationship, Dogs, In vivo, Drug Resistance, Viral, Drug Discovery, medicine, Animals, Humans, Prodrugs, Nucleotide, chemistry.chemical_classification, virus diseases, Esters, Stereoisomerism, Biological activity, Phosphoramidate, Prodrug, digestive system diseases, Rats, Macaca fascicularis, Liver, Biochemistry, chemistry, Mutation, Hepatocytes, Molecular Medicine, Replicon, Sofosbuvir, Uridine Monophosphate, Nucleoside |
| الوصف: | Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2'-Deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the β-d-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e70b0f48ff595e61d3a04db4332b1530 https://doi.org/10.1021/jm100863x |
| رقم الأكسشن: | edsair.doi.dedup.....e70b0f48ff595e61d3a04db4332b1530 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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