A Highly Potent and Selective Caspase 1 Inhibitor that Utilizes a Key 3-Cyanopropanoic Acid Moiety

被引：72

作者：

Boxer, Matthew B. ^{[1
]}

Quinn, Amy M. ^{[1
]}

Shen, Min ^{[1
]}

Jadhav, Ajit ^{[1
]}

Leister, William ^{[1
]}

Simeonov, Anton ^{[1
]}

Auld, Douglas S. ^{[1
]}

Thomas, Craig J. ^{[1
]}

机构：

[1] NHGRI, NIH, NIH Chem Genom Ctr, Rockville, MD 20850 USA

来源：

CHEMMEDCHEM | 2010年 / 5卷 / 05期

基金：

美国国家卫生研究院;

关键词：

caspases; covalent modifiers; cysteine proteases; inhibitors; VRT-043198; VX-765; INTERLEUKIN-1-BETA CONVERTING-ENZYME; CYSTEINE PROTEASES; INFLAMMATORY CASPASES; IMMUNE-RESPONSES; MECHANISM; TETRAZOLES; NITRILES; TARGETS; TBCATB; VX-765;

D O I：

10.1002/cmdc.200900531

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein, we examine the potential of a nitrile-containing propionic acid moiety as an electrophile for covalent attack by the active-site cysteine residue of caspase 1. The syntheses of several cyanopropanate-containing small molecules based on the, optimized peptidic scaffold of prodrug VX-765 were accomplished. These compounds were found to be potent inhibitors of caspase 1 (IC50 values <= 1 nM). Examination of these novel small molecules against a caspase panel demonstrated an impressive degree of selectivity for caspase 1 inhibition over other caspase isozymes. Assessment of hydrolytic stability and selected ADME properties highlighted these agents as potentially useful tools for studying caspase 1 down-regulation in various settings, including in vivo analyses.

引用

页码：730 / 738

页数：9