Substituted 3-Phenyl-1H-Indole TDO Inhibitors Selectivity
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Solution Overview
Problem
Current TDO inhibitors often cross-react with IDO1 and CYP enzymes, leading to adverse drug interactions and toxicity, and lack selectivity, which is a concern for treating diseases associated with increased L-tryptophan degradation.
Innovation Solution
Development of substituted 3-phenyl-1H-indole derivatives that selectively inhibit TDO activity without cross-reacting with IDO1 and CYP, offering potent and selective cellular activity as TDO inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current TDO inhibitors are used, then TDO activity is inhibited, but cross-reactivity with IDO1 and CYP enzymes occurs leading to toxicity and adverse drug interactions
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions on the indole core structure. Different substituents (R1-R6) are placed at specific locations to create localized chemical properties that enhance TDO binding while preventing interactions with IDO1 and CYP enzymes, thereby achieving selectivity without cross-reactivity
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent type, position, and configuration on the indole scaffold. By modifying these chemical parameters, the invention optimizes the inhibitor's selectivity profile to preferentially bind TDO while excluding IDO1 and CYP enzymes, resolving the contradiction between inhibition efficacy and selectivity
2Reliability
If current TDO inhibitors are used, then TDO activity is inhibited, but cross-reactivity with IDO1 and CYP enzymes occurs leading to adverse drug interactions
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions on the indole core structure. Different substituents (R1-R6) are placed at specific locations to create localized chemical properties that enhance TDO binding while preventing interactions with IDO1 and CYP enzymes, thereby achieving selectivity without cross-reactivity
Solution Approach 2:
The patent converts the potential harm of cross-reactivity into benefit by designing a molecular structure that actively prevents unwanted enzyme interactions. The specific substitution pattern on the indole core creates steric and electronic barriers that selectively exclude IDO1 and CYP enzymes, transforming the potential adverse effect of non-specific binding into a beneficial selectivity profile
3Reliability
If current TDO inhibitors are used, then TDO activity is inhibited, but lack of selectivity occurs which is a concern for treating diseases
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions on the indole core structure. Different substituents (R1-R6) are placed at specific locations to create localized chemical properties that enhance TDO binding while preventing interactions with IDO1 and CYP enzymes, thereby achieving selectivity without cross-reactivity
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent type, position, and configuration on the indole scaffold. By modifying these chemical parameters, the invention optimizes the inhibitor's selectivity profile to preferentially bind TDO while excluding IDO1 and CYP enzymes, resolving the contradiction between inhibition efficacy and selectivity
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
The substituted 3-phenyl-1H-indole derivatives effectively inhibit TDO activity with high selectivity over IDO1 and CYP, providing a safe and effective treatment for diseases related to increased L-tryptophan degradation, including cancer and central nervous system disorders.
Implementation Method 1
substituted 3-phenyl-1H-indole compounds which modulate the activity of tryptophan 2,3-dioxygenase, in particular inhibit the activity of tryptophan 2,3-dioxygenase
Data Source
AI summary
The invention relates to a compound of Formula I : Formula I, or pharmaceutically acceptable enantiomers, or salts thereof. The present invention also relates to the use of compounds of Formula (I) as selective inhibitors of tryptophan 2,3-dioxygenase. The invention also relates to the use of the compounds of Formula (I) for the treatment or prevention of cancer and central nervous system disease or disorder, either as a single agent or in combination with other therapies.