Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.,ACS Medicinal Chemistry Letters

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Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-01-11 , DOI: 10.1021/acsmedchemlett.7b00488
Michael G Brant ₁ , Jake Goodwin-Tindall ₁ , Kurt R Stover ₁ , Paul M Stafford ₁ , Fan Wu ₁ , Autumn R Meek ₁ , Paolo Schiavini ₁ , Stephanie Wohnig ₁ , Donald F Weaver _{1,

2,

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Affiliation

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.

中文翻译：

基于苯基咪唑支架的有效吲哚胺2,3-二加氧酶1（IDO1）抑制剂的鉴定。

吲哚胺2，3-二加氧酶（IDO1）的抑制是一种有吸引力的免疫疗法，用于治疗多种癌症。该酶的失调也与其他疾病有关，包括阿尔茨海默氏病和关节炎。在这里，我们报告了两个相关的一系列分子的基于结构的设计：N1-取代的5-吲哚咪唑和N1-取代的5-苯基咪唑。在Van Leusen咪唑合成反应过程中通过亚胺中间体的意外重排获得了后者（和更有效的）系列。计算和结构-活性关系研究都支持两种抑制剂系列的结合模式的证据。

更新日期：2018-01-22

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