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Updated: Nov 25, 2025

Solid-phase Synthesis of [4.4] Spirocyclic Oximes
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Discovery and optimization of substituted oxalamides as novel heme-displacing IDO1 inhibitors

Christoph Steeneck1, Olaf Kinzel1, Simon Anderhub1

  • 1Phenex Pharmaceuticals AG, Waldhofer Str. 104, 69123 Heidelberg, Germany.

Bioorganic & Medicinal Chemistry Letters
|December 17, 2020
PubMed

Since the advent of antibody checkpoint inhibitors as highly efficient drugs for cancer treatment, the development of immunomodulating small molecules in oncology has gained great attention. Drug candidates targeting IDO1, a key enzyme in tryptophan metabolism, are currently under clinical investigation in combination with PD-1/PD-L1 agents as well as with other established anti-tumor therapeutics. A ligand based design approach from hydroxyamidine 4 that aimed at heme-binding IDO1 inhibitors resulted in new compounds with moderate IDO1 potency. A hybrid structure design that made use of the linrodostat structure (2) led to oxalamide derived, heme-displacing IDO1 inhibitors with high cell-based IDO1 potency and a favorable ADME/PK profile.

Keywords:
Cancer immunotherapyHeme-displacerIDO1Indoleamine-2,3-dioxygenase-1OxalamidesTryptophan-kynurenine-AhR-pathway

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