The design of potent hydrazones and disuffides as Cathepsin S inhibitors

被引:23
作者
Cywin, CL
Firestone, RA
McNeil, DW
Grygon, CA
Crane, KM
White, DM
Kinkade, PR
Hopkins, JL
Davidson, W
Labadia, ME
Wildeson, J
Morelock, MM
Peterson, JD
Raymond, EL
Brown, ML
Spero, DM
机构
[1] Boehringer Ingelheim Pharmaceut Inc, Dept Med Chem, Ctr Res & Dev, Ridgefield, CT 06877 USA
[2] Boehringer Ingelheim Pharmaceut Inc, Dept Biol, Ctr Res & Dev, Ridgefield, CT 06877 USA
[3] Boehringer Ingelheim Pharmaceut Inc, Dept Pharmacol, Ctr Res & Dev, Ridgefield, CT 06877 USA
关键词
D O I
10.1016/S0968-0896(02)00468-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The design and synthesis of dipeptidyl disulfides and dipeptidyl benzoylhydrazones as selective inhibitors of the cysteine protease Cathepsin S are described. These inhibitors were expected to form a slowly reversible covalent adduct of the active site cysteine of Cathepsin S. Formation of the initial adduct was confirmed by mass spectral analysis. The nature and mechanism of these adducts was explored. Kinetic analysis of the benzoyl hydrazones indicate that these inhibitors are acting as irreversible inhibitors of Cathepsin S. Additionally, the benzoylhydrazones were shown to be potent inhibitors of Cathepsin S processing of Class II associated invariant peptide both in vitro and in vivo. (C) 2002 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:733 / 740
页数:8
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