TDO and IDO Inhibitors to Reduce Neurotoxic Metabolite Accumulation

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Solution Overview

Problem

Current treatments for diseases and disorders related to tryptophan metabolism, such as cancer, inflammatory conditions, infectious diseases, and central nervous system disorders, are limited by the immunosuppressive effects of tryptophan catabolism mediated by TDO and IDO enzymes, which deplete tryptophan and accumulate neurotoxic metabolites, leading to immune suppression and tissue damage.

Innovation Solution

Development of inhibitors targeting TDO and/or IDO enzymes to block the conversion of tryptophan to N-formylkynurenine, thereby reducing the accumulation of immunosuppressive metabolites and restoring immune function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TDO and IDO enzymes are active to regulate tryptophan metabolism, then tryptophan catabolism is maintained for immune suppression and tissue protection, but immune function is suppressed and neurotoxic metabolites accumulate

Engineering Contradiction:

Improveimmune functionVSAvoidneurotoxic metabolite accumulation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent extracts and removes the harmful metabolic pathway by developing inhibitors that block TDO and IDO enzymes, preventing the conversion of tryptophan to neurotoxic kynurenine metabolites while preserving essential immune regulatory functions

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the metabolic parameters by inhibiting TDO and IDO enzyme activity, thereby altering the tryptophan catabolism pathway to reduce neurotoxic metabolite production while maintaining tryptophan depletion-mediated immune suppression

Inventive Principle:

Principle #35Parameter changes

2Reliability

If tryptophan catabolism is enhanced to suppress immune responses and prevent immunopathology, then immune regulation is improved, but cancer progression and tissue damage are promoted

Engineering Contradiction:

Improveimmune regulationVSAvoidcancer progression

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent inverts the therapeutic approach by instead of enhancing tryptophan catabolism for immune suppression, it blocks TDO and IDO enzymes to prevent neurotoxic metabolite accumulation that promotes cancer progression, thereby maintaining immune regulation while preventing tissue damage

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent converts the harmful effect of tryptophan catabolism into a beneficial outcome by selectively inhibiting TDO and IDO enzymes to reduce neurotoxic metabolite production, thereby transforming a pathway that promotes cancer into one that supports immune function and prevents tissue damage

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Inhibitors of TDO and/or IDO can restore immune function, reduce neurotoxic metabolite levels, and improve outcomes in a wide range of diseases, including cancer, infectious diseases, and CNS disorders, by breaking the feedback loop of tryptophan catabolism and enhancing immune responses.

Implementation Method 1

Both enzymes catalyze the oxidative cleavage of the 2,3 double bond in the indole ring, converting tryptophan to N-formylkynurenine

Methodology Applied

Scientific EffectOxidative cleavage: Oxidation

Data Source

PatentEP3215156B1Inhibitors of tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase

Publication Date: 2025.09.24 IOMET PHARMA

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AI summary

Provided is a tryptophan-2,3-dioxygenase (TDO) and/or indoleamine-2,3-dioxygenase (IDO) inhibitor compound for use in medicine, which compound comprises formula (I) wherein X1, and X2 may be the same or different and each is independently selected from C, N, O and S; X3, X4, X5, and X6 may be the same or different and each is independently selected from C and N; each bond represented by a dotted line may be present or absent, provided that at least one such bond is present; R1, R2, R3, R4, R5 and R6 may be present or absent and may be the same or different and each is independently selected from H and a substituted or unsubstituted organic group, provided that the number of R1, R2, R3, R4, R5 and R6 groups present is such that the respective valencies of X1, X2, X3, X4, X5, and X6 are maintained; and wherein at least one of R5 and R6 comprises a group Y, wherein Y is a group having a formula selected from (II), (III), (IV), (V), (VI), (VII) wherein L may be present or absent, and may be a substituted or unsubstituted organic linking group; R31 and R32 may be the same or different and are selected from H and a substituted or unsubstituted organic group; each R34 may be the same or different and is selected from H and a substituted or unsubstituted organic group; R35 is selected from a substituted or unsubstituted alcohol group or ether group; each R36 may be the same or different and is selected from H and a substituted or unsubstituted organic group; X7 may be selected from C and N; X8, X9, X10, X11, X12, X13, X14, X15 and X16 may be the same or different and each is independently selected from C, N, O and S; each bond represented by a dotted line may be present or absent; and each R313 may be the same or different and is selected from H and a substituted or unsubstituted organic group.