Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold

被引：26

作者：

Brant, Michael G. ^{[1
]}

Goodwin-Tindall, Jake ^{[1
]}

Stover, Kurt R. ^{[1
]}

Stafford, Paul M. ^{[1
]}

Wu, Fan ^{[1
]}

Meek, Autumn R. ^{[1
]}

Schiavini, Paolo ^{[1
]}

Wohnig, Stephanie ^{[1
]}

Weaver, Donald F. ^{[1
,2
,3
]}

机构：

[1] Univ Hlth Network, Krembil Res Inst, 60 Leonard Ave, Toronto, ON M5T 2S8, Canada

[2] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada

[3] Univ Toronto, Dept Med, Toronto, ON M5G 2C4, Canada

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 02期

关键词：

Immunooncology; IDO1; inhibitors; structure-based drug design; molecular modeling; CRYSTAL-STRUCTURES; RATIONAL DESIGN; TRYPTOPHAN; MECHANISM; DISCOVERY; BINDING; DERIVATIVES; CHALLENGES; FLUORINE;

D O I：

10.1021/acsmedchemlett.7b00488

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N1-substituted 5-indoleimidazoles and N1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.

引用

页码：131 / 136

页数：6

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