Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2

被引：58

作者：

Kloeck, Cornelius ^{[1
]}

Jin, Xi ^{[1
]}

Choi, Kihang ^{[1
]}

Khosla, Chaitan ^{[1
]}

Madrid, Peter B. ^{[2
]}

Spencer, Andrew ^{[3
]}

Raimundo, Brian C. ^{[4
]}

Boardman, Paul ^{[4
]}

Lanza, Guido ^{[4
]}

Griffin, John H. ^{[4
]}

机构：

[1] Stanford Univ, Dept Chem, Stanford, CA 94305 USA

[2] SRI Int, Dept Med Chem, Menlo Pk, CA 94025 USA

[3] Celiac Sprue Res Fdn, Palo Alto, CA 94306 USA

[4] Numerate Inc, San Bruno, CA 94066 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 09期

关键词：

Transglutaminase; 2; Oxoindole; Celiac sprue; Structure-activity relationships; Allostery; HUMAN TISSUE TRANSGLUTAMINASE; NEURODEGENERATIVE DISORDERS; SELECTIVE INHIBITORS; DERIVATIVES; KETONES; POTENT; CONSTRUCTION; ACTIVATION; FIBROSIS; DISEASE;

D O I：

10.1016/j.bmcl.2010.12.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K(i) values below 1.0 mu M in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2692 / 2696

页数：5

共 40 条

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