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
| Autor: | 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 |
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| Rok vydání: | 2010 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 53:7202-7218 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100863x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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