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

Olaf Kinzel; Christoph Steeneck; Simon Anderhub; Martin Hornberger; Sheena Pinto; Barbara Morschhaeuser; Michael Albers; Christina Sonnek; Yansong Wang; Aurélie Mallinger; Marta Czekańska; Thomas Hoffmann

doi:10.1016/j.bmcl.2020.127738

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

Bioorg Med Chem Lett. 2021 Feb 1:33:127738. doi: 10.1016/j.bmcl.2020.127738. Epub 2020 Dec 11.

Affiliations

¹ Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany. Electronic address: acr8172@gmail.com.
² Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany. Electronic address: c.steeneck@t-online.de.
³ Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.

PMID: 33316404
DOI: 10.1016/j.bmcl.2020.127738

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).

Keywords: Cancer immunotherapy; Heme-displacer; IDO1; Indoleamine-2,3-dioxygenase-1; Spirofused; Tryptophan-kynurenine-AhR-pathway.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Bridged Bicyclo Compounds / chemical synthesis
Bridged Bicyclo Compounds / chemistry
Bridged Bicyclo Compounds / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Kynurenine / antagonists & inhibitors
Kynurenine / biosynthesis
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Mice
Molecular Structure
Oxamic Acid / chemical synthesis
Oxamic Acid / chemistry
Oxamic Acid / pharmacology*
Structure-Activity Relationship

Substances

Amides
Bridged Bicyclo Compounds
Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase
Lipopolysaccharides
Kynurenine
Oxamic Acid