Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design

被引：105

作者：

Greenspan, PD ^{[1
]}

Clark, KL ^{[1
]}

Tommasi, RA ^{[1
]}

Cowen, SD ^{[1
]}

McQuire, LW ^{[1
]}

Farley, DL ^{[1
]}

van Duzer, JH ^{[1
]}

Goldberg, RL ^{[1
]}

Zhou, HH ^{[1
]}

Du, ZM ^{[1
]}

Fitt, JJ ^{[1
]}

Coppa, DE ^{[1
]}

Fang, Z ^{[1
]}

Macchia, W ^{[1
]}

Zhu, LJ ^{[1
]}

Capparelli, MP ^{[1
]}

Goldstein, R ^{[1
]}

Wigg, AM ^{[1
]}

Doughty, JR ^{[1
]}

Bohacek, RS ^{[1
]}

Knap, AK ^{[1
]}

机构：

[1] Nova Pharmaceut Corp, Arthrit & Bone Metab Res, Summit, NJ 07901 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2001年 / 44卷 / 26期

关键词：

D O I：

10.1021/jm010206q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH2CN (19, IC50 = 62 muM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P-1, P-2, and P-3 substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S-2' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.

引用

页码：4524 / 4534

页数：11

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