Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design

被引：36

作者：

Du, Jinfa ^{[1
]}

Chun, Byoung-Kwon ^{[1
]}

Mosley, Ralph T. ^{[1
]}

Bansal, Shalini ^{[1
]}

Bao, Haiying ^{[1
]}

Espiritu, Christine ^{[1
]}

Lam, Angela M. ^{[1
]}

Murakami, Eisuke ^{[1
]}

Niu, Congrong ^{[1
]}

Steuer, Holly M. Micolochick ^{[1
]}

Furman, Phillip A. ^{[1
]}

Sofia, Michael J. ^{[1
]}

机构：

[1] Pharmasset Inc, Princeton, NJ 08540 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 05期

关键词：

HEPATITIS-C-VIRUS; DEPENDENT RNA-POLYMERASE; ANTIVIRAL ACTIVITY; ANALOGS; REPLICATION; INHIBITION; PRODRUG; POTENT; 2'-C-METHYLCYTIDINE; RIBONUCLEOSIDES;

D O I：

10.1021/jm401224y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Conformationally restricted 2'-spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2'-oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC50 = 8.48 mu M. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2'-oxetane 2-amino-6-O-methylpurine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase.

引用

收藏

页码：1826 / 1835

页数：10

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