2′-Deoxy-2′-α-fluoro-2′-β-C-methyl 3′,5′-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: Discovery of PSI-352938

被引：47

作者：

Reddy, P. Ganapati ^{[1
]}

Bao, Donghui ^{[1
]}

Chang, Wonsuk ^{[1
]}

Chun, Byoung-Kwon ^{[1
]}

Du, Jinfa ^{[1
]}

Nagarathnam, Dhanapalan ^{[1
]}

Rachakonda, Suguna ^{[1
]}

Ross, Bruce S. ^{[1
]}

Zhang, Hai-Ren ^{[1
]}

Bansal, Shalini ^{[1
]}

Espiritu, Christine L. ^{[1
]}

Keilman, Meg ^{[1
]}

Lam, Angela M. ^{[1
]}

Niu, Congrong ^{[1
]}

Steuer, Holly Micolochick ^{[1
]}

Furman, Phillip A. ^{[1
]}

Otto, Michael J. ^{[1
]}

Sofia, Michael J. ^{[1
]}

机构：

[1] Pharmasset Inc, Princeton, NJ 08540 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 24期

关键词：

Antiviral; HCV; Nucleoside; Prodrug; Cyclic Phosphate; C VIRUS-REPLICATION; ANTIVIRAL ACTIVITY; HUH-7; CELLS; EFFICIENT; REPLICON; RING; MONOPHOSPHATE; DESIGN;

D O I：

10.1016/j.bmcl.2010.10.035

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel 2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938). (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7376 / 7380

页数：5

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