Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)

被引：64

作者：

Hare, Alissa A. ^{[2
]}

Leng, Lin ^{[1
]}

Gandavadi, Sunilkumar ^{[2
]}

Du, Xin ^{[1
]}

Cournia, Zoe ^{[2
]}

Bucala, Richard ^{[1
]}

Jorgensen, William L. ^{[2
]}

机构：

[1] Yale Univ, Dept Med, Sch Med, New Haven, CT 06520 USA

[2] Yale Univ, Dept Chem, New Haven, CT 06520 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 19期

基金：

美国国家卫生研究院;

关键词：

MIF; Inhibitor design; Protein-protein interactions; Cytokine; Inflammatory disease; RHEUMATOID-ARTHRITIS; BIOMOLECULAR SYSTEMS; CANCER CELLS; TAUTOMERASE; DISCOVERY; GROWTH; COMPONENT; DOCKING; MOUSE; MODEL;

D O I：

10.1016/j.bmcl.2010.07.129

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The cytokine MIF is involved in inflammation and cell proliferation via pathways initiated by its binding to the transmembrane receptor CD74. MIF also exhibits keto-enol tautomerase activity, believed to be vestigial in mammals. Starting from a 1 mu M hit from virtual screening, substituted benzoxazol-2-ones have been discovered as antagonists with IC50 values as low as 7.5 nM in a tautomerase assay and 80 nM in a MIF-CD74 binding assay. Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5811 / 5814

页数：4

共 25 条

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