Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S

被引：13

作者：

Chatterjee, Arnab K. ^{[1
]}

Liu, Hong ^{[1
]}

Tully, David C. ^{[1
]}

Guo, Jianhua ^{[1
]}

Epple, Robert ^{[1
]}

Russo, Ross ^{[1
]}

Williams, Jennifer ^{[1
]}

Roberts, Michael ^{[1
]}

Tuntland, Tove ^{[1
]}

Chang, Jonathan ^{[1
]}

Gordon, Perry ^{[1
]}

Hollenbeck, Thomas ^{[1
]}

Tumanut, Christine ^{[1
]}

Li, Jun ^{[1
]}

Harris, Jennifer L. ^{[1
]}

机构：

[1] GNF, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 10期

关键词：

cathepsin S; lysosomal proteases; succinamides;

D O I：

10.1016/j.bmcl.2007.02.049

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues. (c) 2007 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2899 / 2903

页数：5

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