Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

被引：22

作者：

Ameriks, Michael K. ^{[1
]}

Bembenek, Scott D. ^{[1
]}

Burdett, Matthew T. ^{[2
]}

Choong, Ingrid C. ^{[2
]}

Edwards, James P. ^{[1
]}

Gebauer, Damara ^{[1
]}

Gu, Yin ^{[1
]}

Karlsson, Lars ^{[1
]}

Purkey, Hans E. ^{[2
]}

Staker, Bart L. ^{[3
]}

Sun, Siquan ^{[1
]}

Thurmond, Robin L. ^{[1
]}

Zhu, Jian ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, San Diego, CA 92121 USA

[2] Sunesis Pharmaceut, San Francisco, CA 94080 USA

[3] deCODE Biostruct Inc, Bainbridge Isl, WA 98110 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 14期

关键词：

Cathepsin; Protease; Tethering; X-ray crystallography; Fragment-based screening; ANTIGEN PRESENTATION; WATER-MOLECULES; DISCOVERY; IDENTIFICATION; ANTIBODY; MICE;

D O I：

10.1016/j.bmcl.2010.05.086

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

A pyridazin-4-one fragment 4 (hCatS IC(50) = 170 mu M) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50) = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50) = 60 nM) and 27 (hCatS IC(50) = 40 nM). (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：4060 / 4064

页数：5

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