Synthesis and Anti-HCV Activities of 4′-Fluoro-2′-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4′-Fluoro-2′-C-methyluridine 5′-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

被引：35

作者：

Wang, Guangyi ^{[1
]}

Dyatkina, Natalia ^{[1
]}

Prhavc, Marija ^{[1
]}

Williams, Caroline ^{[1
,3
]}

Serebryany, Vladimir ^{[1
,3
]}

Hu, Yujian ^{[2
]}

Huang, Yongfei ^{[2
]}

Wan, Jinqiao ^{[2
,4
]}

Wu, Xiangyang ^{[2
]}

Deval, Jerome ^{[1
,3
]}

Fung, Amy ^{[1
]}

Jin, Zhinan ^{[1
]}

Fan, Hua ^{[1
,3
]}

Shaw, Kenneth ^{[1
]}

Kang, Hyunsoon ^{[1
]}

Zhang, Qingling ^{[1
,3
]}

Tam, Yuen ^{[1
]}

Stoycheva, Antitsa ^{[1
,3
]}

Jekle, Andreas ^{[1
,3
]}

Smith, David B. ^{[1
,3
]}

Beigelman, Leonid ^{[1
,3
]}

机构：

[1] Janssen BioPharma Inc, San Francisco, CA 94080 USA

[2] WuXi AppTec, Dept Med Chem, Shanghai 200131, Peoples R China

[3] Aligos Therapeut, 1 Corp Dr, San Francisco, CA 94080 USA

[4] HitGen, Floor 7-10,Bldg B3,Tianfu Life Sci Pk 88, Chengdu 610041, Sichuan, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 09期

关键词：

INHIBITOR; SOFOSBUVIR; DESIGN; RNA;

D O I：

10.1021/acs.jmedchem.9b00143

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the synthesis and biological evaluation of a series of 4'-fluoro-2'-C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

引用

页码：4555 / 4570

页数：16

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