Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold. (1st February 2021)

• Record Type: Journal Article
• Authors: Kinzel, Olaf; Steeneck, Christoph; Anderhub, Simon; Hornberger, Martin; Pinto, Sheena; Morschhaeuser, Barbara; Albers, Michael; Sonnek, Christina; Wang, Yansong; Mallinger, Aurélie; Czekańska, Marta; Hoffmann, Thomas
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 33(2021)
• Publication Date: 2021-02-01
• Subjects: Indoleamine-2, 3-dioxygenase-1 -- IDO1 -- Heme-displacer -- Spirofused -- Tryptophan-kynurenine-AhR-pathway -- Cancer immunotherapy; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127738
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1 ).