Development of a series of novel o-phenylenediamine-based indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2018-02, Vol.28 (4), p.732-736
• Main Authors: Williams, David K., Markwalder, Jay A., Balog, Aaron J., Chen, Bin, Chen, Libing, Donnell, Jennifer, Haque, Lauren, Hart, Amy C., Mandal, Sunil K., Nation, Andrew, Shan, Weifang, Vite, Gregory D., Covello, Kelly, Hunt, John T., Jure-Kunkel, Maria N., Seitz, Steven P.
• Format: Article
• Language: English
• Subjects: Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; HeLa Cells; Humans; IDO; IDO1; Immuno-oncology; Indoleamine 2,3-dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Kynurenine; Microsomes, Liver - metabolism; Phenylenediamines - chemical synthesis; Phenylenediamines - chemistry; Phenylenediamines - metabolism; Phenylenediamines - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.01.010

[Display omitted] A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. Compound 19 demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .