Selection, Preparation, and Evaluation of Small-Molecule Inhibitors of Toll-Like Receptor 4

被引：29

作者：

Bevan, Douglas E. ^{[1
]}

Martinko, Alexander J. ^{[1
]}

Loram, Lisa C. ^{[2
,3
]}

Stahl, Joshua A. ^{[1
]}

Taylor, Frederick R. ^{[2
]}

Joshee, Sampada ^{[1
]}

Watkins, Linda R. ^{[2
,3
]}

Yin, Hang ^{[1
,3
]}

机构：

[1] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA

[2] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA

[3] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2010年 / 1卷 / 05期

基金：

美国国家卫生研究院;

关键词：

Toll-like receptor; glial cells; signal transduction; protein-protein interactions; synthesis; TLR4-MD-2; COMPLEX; MANNICH-BASES; AGENTS; LIPOPOLYSACCHARIDE; ANTAGONIST; CHEMISTRY; TLR4; PAIN;

D O I：

10.1021/ml100041f

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Toll-like receptor 4 (TLR4), a membrane-spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein, we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation.

引用

页码：194 / 198

页数：5

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