Discovery of Potent Competitive Inhibitors of Indoleamine 2,3-Dioxygenase with in Vivo Pharmacodynamic Activity and Efficacy in a Mouse Melanoma Model

被引：200

作者：

Yue, Eddy W. ^{[1
]}

Douty, Brent ^{[1
]}

Wayland, Brian ^{[1
]}

Bower, Michael ^{[1
]}

Liu, Xiangdong ^{[1
]}

Leffet, Lynn ^{[1
]}

Wang, Qian ^{[1
]}

Bowman, Kevin J. ^{[1
]}

Hansbury, Michael J. ^{[1
]}

Liu, Changnian ^{[1
]}

Wei, Min ^{[1
]}

Li, Yanlong ^{[1
]}

Wynn, Richard ^{[1
]}

Burn, Timothy C. ^{[1
]}

Koblish, Holly K. ^{[1
]}

Fridman, Jordan S. ^{[1
]}

Metcalf, Brian ^{[1
]}

Scherle, Peggy A. ^{[1
]}

Combs, Andrew P. ^{[1
]}

机构：

[1] Incyte Corp, Expt Stn, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 23期

关键词：

IMMUNE TOLERANCE; DENDRITIC CELLS; EXIGUAMINE-A; SUPPRESSION; CANCER; TARGET;

D O I：

10.1021/jm900518f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (I DO). Optimization led to the identification of 5l, which is a potent (HeLa IC50 = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of I DO, as measured by decreased kynurenine levels (> 50%) in plasma and dose dependent efficacy in mice hearing GM-CSF-secreting B16 melanoma tumors.

引用

页码：7364 / 7367

页数：4

共 23 条

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