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Inhibition of the Kynurenine Pathway of Tryptophan Metabolism

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Targeting the Broadly Pathogenic Kynurenine Pathway

Abstract

This chapter summarizes the current state-of-the-art of inhibitors of the kynurenine pathway. After a brief presentation regarding the kynurenine pathway itself and the enzymes involved, the main series of inhibitors that were discovered are presented by targets. Among the enzymes investigated in the present study are the indoleamine 2,3-dioxygenases IDO1 and TDO, the kynurenine-aminotransferases (KATs), the kynureninase, the kynurenine 3-monooxygenase, and the 3-hydroxyanthranilic monooxygenase. All these enzymes are responsible for the formation of tryptophan metabolites, collectively called the kynurenines and thus constitute very interesting targets in various diseases.

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Abbreviations

1MT:

1-Methyl-tryptophan

3-HAO:

3-Hydroxyanthranilic monooxygenase

CNS:

Central nervous system

HTS:

High throughput screening

IDO1:

Indoleamine 2,3-dioxygenase 1

KATs:

Kynurenine aminotransferases

KMO:

Kynurenine-3-monooxygenase (also called kynurenine 3-hydroxylase)

LE:

Ligand efficiency

mM:

Millimolar

MTH-Trp:

N-methyl-thiohydantoine-tryptophane

NAD:

Nicotinamide Adenine Dinucleotide

nM:

Nanomolar

PIM:

4-Phenylimidazole

PLP:

Pyridoxal-5′-phosphate

SAR:

Structure–activity relationships

TDO:

Tryptophan 2,3-dioxygenase

μM:

Micromolar

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Acknowledgments

RF wishes to thank Dr. Eduard Dolusic for fruitful discussions.

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  1. Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCL), 73 avenue Mounier, B1.73.10, 1200, Brussel, Belgium

    Raphaël Frédérick

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  1. Raphaël Frédérick
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Correspondence to Raphaël Frédérick .

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  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Frédérick, R. (2015). Inhibition of the Kynurenine Pathway of Tryptophan Metabolism. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_29

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