Structural Optimization of Azadipeptide Nitriles Strongly Increases Association Rates and Allows the Development of Selective Cathepsin Inhibitors

被引：71

作者：

Frizler, Maxim ^{[1
]}

Lohr, Friederike ^{[1
]}

Furtmann, Norbert ^{[1
]}

Klas, Julia ^{[1
]}

Gutschow, Michael ^{[1
]}

机构：

[1] Univ Bonn, Inst Pharmaceut, D-53121 Bonn, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 01期

关键词：

CYSTEINE CATHEPSINS; POTENT;

D O I：

10.1021/jm101272p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using the example of cathepsin K, we demonstrate the design of highly potent and selective azadipeptide nitrite inhibitors A systematic scan with respect to P2 and P3 substituents was carried out Structural modifications strongly affected the enzyme-inhibitor association (but not dissociation) rate A combination of optimized P2 and P3 substituents with a methylation of the P3-P2 amide linker resulted in the picomolar cathepsin K inhibitor 19 with remarkable selectivity over cathepsins L, B, and S

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页码：396 / 400

页数：5

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