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

Authors :: Kinzel O
Steeneck C
Anderhub S
Hornberger M
Pinto S
Morschhaeuser B
Albers M
Sonnek C
Wang Y
Mallinger A
Czekańska M
Hoffmann T
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Feb 01; Vol. 33, pp. 127738. Date of Electronic Publication: 2020 Dec 11.
Publication Year :: 2021
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 IC <subscript>50</subscript> 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).<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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