Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold

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).

Automated summary

Through structural modification, a novel class of highly potent IDO1-specific inhibitors was identified, with representative compound 18 showing strong inhibitory activity in cellular and whole blood assays. Pharmacokinetic profiling in mice demonstrated improved clearance compared to the original compound, and in a mouse pharmacodynamic model, compound 18 significantly suppressed kynurenine production induced by lipopolysaccharide. Hepatocyte data suggested human clearance of compound 18 is similar to linrodostat.