Design, Synthesis and Biological Evaluation of a Library of Thiocarbazates and Their Activity as Cysteine Protease Inhibitors

被引：1

作者：

Liu, Zhuqing ^{[1
,2
]}

Myers, Michael C. ^{[1
,2
]}

Shah, Parag P. ^{[2
,3
]}

Beavers, Mary Pat ^{[2
,3
]}

Benedetti, Phillip A. ^{[1
,2
]}

Diamond, Scott L. ^{[2
,3
]}

Smith, Amos B., III ^{[1
,2
]}

Huryn, Donna M. ^{[1
,2
]}

机构：

[1] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA

[2] Univ Penn, Penn Ctr Mol Discovery, Vagelos Res Labs 1024, Philadelphia, PA 19104 USA

[3] Univ Penn, Inst Med & Engn, Vagelos Res Labs 1024, Philadelphia, PA 19104 USA

来源：

COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING | 2010年 / 13卷 / 04期

关键词：

Thiocarbazates; cathepsin B; cathepsin S; cathepsin L; cysteine protease inhibitor; library; HUMAN CATHEPSIN-L; MOLECULAR DOCKING; PROTEINASES; SITE; SPECIFICITY; KETONES; SERINE; PAPAIN;

D O I：

10.2174/138620710791054303

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.

引用

页码：337 / 351

页数：15

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