Identification and Characterization of Small Molecule Modulators of the Epstein-Barr Virus-Induced Gene 2 (EBI2) Receptor

被引：51

作者：

Gessier, Francois ^{[1
]}

Preuss, Inga ^{[1
]}

Yin, Hong ^{[2
]}

Rosenkilde, Mette M. ^{[3
]}

Laurent, Stephane ^{[1
]}

Endres, Ralf ^{[1
]}

Chen, Yu A. ^{[2
]}

Marsilje, Thomas H. ^{[2
]}

Seuwen, Klaus ^{[1
]}

Nguyen, Deborah G. ^{[2
]}

Sailer, Andreas W. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

[2] Novartis Res Fdn GNF, Genom Inst, San Diego, CA 92121 USA

[3] Univ Copenhagen, Fac Hlth & Med Sci, Dept Neurosci & Pharmacol, Lab Mol Pharmacol, DK-2200 Copenhagen, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 08期

关键词：

OXYSTEROL-BINDING; 7-TRANSMEMBRANE RECEPTOR; CELL-MIGRATION; ROR-ALPHA; LIGAND; CHOLESTEROL; ATHEROSCLEROSIS; ACTIVATORS; DISCOVERY; ANGSTROM;

D O I：

10.1021/jm4019355

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：

Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) (Nature 2011, 475, 524; 519). EBI2 is highly expressed in immune cells (J. Biol. Chem. 2006, 281, 13199), and its activation has been shown to be critical for the adaptive immune response and has been genetically linked to autoimmune diseases such as type I diabetes (Nature 2010, 467, 460). Here we describe the isolation of a potent small molecule antagonist for the EBI2 receptor. First, we identified a small molecule agonist NIBR51 (1), which enabled 0 identification of inhibitors of receptor activation. One antagonist called NIBR127 (2) was used as a starting point for a medicinal chemistry. campaign, which yielded NIBR189 (4m). This compound was extensively characterized in binding and various functional signaling assays. Furthermore, we have used 4m to block migration of a monocyte cell line called U937, suggesting a functional role of the oxysterol/EBI2 pathway in these immune cells.

引用

页码：3358 / 3368

页数：11

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