1402838-89-4Relevant articles and documents
Discovery of clinical candidate (1 R,4 r)-4-((R)-2-((S)-6-Fluoro-5 H-imidazo[5,1-A[isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1
Kumar, Sanjeev,Waldo, Jesse P.,Jaipuri, Firoz A.,Marcinowicz, Agnieszka,Van Allen, Clarissa,Adams, James,Kesharwani, Tanay,Zhang, Xiaoxia,Metz, Richard,Oh, Angela J.,Harris, Seth F.,Mautino, Mario R.
, p. 6705 - 6733 (2019/08/20)
A novel class of 5-substituted 5H-imidazo[5,1-a]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5H-imidazo[5,1-a]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.
Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies
Zou, Yi,Wang, Fang,Wang, Yan,Sun, Qirui,Hu, Yue,Li, Yuezhen,Liu, Wen,Guo, Wenjie,Huang, Zhangjian,Zhang, Yihua,Xu, Qiang,Lai, Yisheng
, p. 293 - 304 (2017/10/05)
Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN-γ production, and reduce the numbers of Foxp3+ regulatory T cells. Finally, induced fit docking (IFD) and quantum mechanics/molecular mechanics (QM/MM) calculation were performed to understand the interactions of these compounds to IDO1 protein, which provided a comprehensive guide for further structural modification and optimization.
A deuterated of the IDO inhibitor and its preparation and use (by machine translation)
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, (2017/04/22)
The invention provides a deuterated of the IDO inhibitor and its preparation and use, as shown in formula I provide compound or its crystalline form, a pharmaceutically acceptable salt, hydrate or solvate. The preparation of the compound or its crystalline form, a pharmaceutically acceptable salt, hydrate or solvate, can be regarded as the IDO inhibitor, can be used for the treatment of IDO related diseases, in particular cancer, viral infection, depression, neurodegenerative disease, trauma, age-related cataract, organ transplant rejection and autoimmune diseases. (by machine translation)
