Discovery and SAR studies of a novel series of noncovalent cathepsin S inhibitors

被引：42

作者：

Gustin, DJ ^{[1
]}

Sehon, CA ^{[1
]}

Wei, JM ^{[1
]}

Cai, H ^{[1
]}

Meduna, SP ^{[1
]}

Khatuya, H ^{[1
]}

Sun, SQ ^{[1
]}

Gu, Y ^{[1
]}

Jiang, W ^{[1
]}

Thurmond, RL ^{[1
]}

Karlsson, L ^{[1
]}

Edwards, JP ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 06期

关键词：

cathepsin S; cysteine protease inhibitor;

D O I：

10.1016/j.bmcl.2005.01.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of competitive, reversible cathepsin S (Cats) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of Cats inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：1687 / 1691

页数：5

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