Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase

被引：139

作者：

Kumar, Sanjeev ^{[1
]}

Jaller, Daniel ^{[2
]}

Patel, Bhumika ^{[1
]}

LaLonde, Judith M. ^{[1
]}

DuHadaway, James B. ^{[2
]}

Malachowski, William P. ^{[1
]}

Prendergast, George C. ^{[2
,3
,4
]}

Muller, Alexander J. ^{[2
]}

机构：

[1] Bryn Mawr Coll, Dept Chem, Bryn Mawr, PA 19010 USA

[2] Lankenau Inst Med Res, Wynnewwod, PA 19096 USA

[3] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19104 USA

[4] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19104 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 16期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1021/jm800512z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. With the goal of developing more potent IDO inhibitors, a systematic study of 4-phenylimidazole (4-PI) derivatives was undertaken. Computational docking experiments guided design and synthesis efforts with analogues of 4-PI. In particular, three interactions of 4-PI analogues with IDO were studied: the active site entrance, the interior of the active site, and the heme iron binding. The three most potent inhibitors (1, 17, and 18) appear to exploit interactions with C129 and S167 in the interior of the active site. All three inhibitors are approximately 10-fold more potent than 4-PI. The study represents the first example of enzyme inhibitor development with the recently reported crystal structure of IDO and offers important lessons in the search for more potent inhibitors.

引用

页码：4968 / 4977

页数：10

共 71 条

[31] Automated process research and the optimization of the synthesis of 4(5)-(3-pyridyl)imidazole [J].