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
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- 作者：Michael J. Sofia ; Donghui Bao ; Wonsuk Chang ; Jinfa Du ; Dhanapalan Nagarathnam ; Suguna Rachakonda ; P. Ganapati Reddy ; Bruce S. Ross ; Peiyuan Wang ; Hai-Ren Zhang ; Shalini Bansal ; Christine Espiritu ; Meg
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：October 14, 2010
- 年：2010
- 卷：53
- 期：19
- 页码：7202-7218
- 全文大小：1102K
- 年卷期：v.53,no.19(October 14, 2010)
- ISSN：1520-4804
文摘
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.