Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors

被引：26

作者：

Yang, Hanbiao ^{[1
]}

Hendricks, Robert T. ^{[1
]}

Arora, Nidhi ^{[1
]}

Nitzan, Dov ^{[1
]}

Yee, Calvin ^{[1
]}

Lucas, Matthew C. ^{[1
]}

Yang, Yanli ^{[2
]}

Fung, Amy ^{[2
]}

Rajyaguru, Sonal ^{[2
]}

Harris, Seth F. ^{[3
]}

Leveque, Vincent J. P. ^{[2
]}

Hang, Julie Q. ^{[2
]}

Pogam, Sophie Le ^{[2
]}

Reuter, Deborah ^{[1
]}

Tavares, Gisele A. ^{[3
]}

机构：

[1] Roche Palo Alto LLC, Dept Med Chem, Palo Alto, CA 94304 USA

[2] Roche Palo Alto LLC, Viral Dis Discovery & Translat Area, Palo Alto, CA 94304 USA

[3] Roche Palo Alto LLC, Discovery Technol Xray Crystallog Grp, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 15期

关键词：

Amide bioisostere; Modeling; Synthesis; HCV; NS5B polymerase; Thumb; Mutant; 3mt5; X-ray structure; PDB; Ruthenium catalyst; HEPATITIS-C; HCVNS5B POLYMERASE; CRYSTAL-STRUCTURES; DISCOVERY; MECHANISM; POTENT; CYCLOADDITION; REPLICATION; BINDING;

D O I：

10.1016/j.bmcl.2010.06.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：4614 / 4619

页数：6

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