N-cyano-7-azanorbornane Selective USP30 Inhibition
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Solution Overview
Problem
Current approaches lack selective inhibitors for USP30, a deubiquitinating enzyme implicated in mitochondrial dysfunction and neurodegenerative diseases, necessitating the development of compounds that can modulate USP30 activity with greater specificity and efficacy compared to other cysteine proteases.
Innovation Solution
Substituted N-cyano-7-azanorbornane compounds are developed, which exhibit selective inhibition of USP30 activity, offering at least 10-fold greater inhibition compared to Cathepsin K or S and other DUB enzymes, and are designed for pharmaceutical compositions to treat mitochondrial dysregulation and neurodegenerative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current deubiquitinating enzyme inhibitors are used, then general DUB inhibition is achieved, but selective inhibition of USP30 is not obtained
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at particular positions on the bicyclic core structure. Different substituents (R1-R6) are placed at specific locations to create localized interactions with USP30, enhancing selectivity for this specific enzyme while maintaining a relatively simple overall molecular framework.
Solution Approach 2:
The patent employs parameter changes by systematically varying substituent types, positions, and configurations on the bicyclic core. By changing these molecular parameters (substituent identity, position, stereochemistry), the compound achieves high selectivity for USP30 without requiring complex multi-component structures.
2Reliability
If selective USP30 inhibition is achieved through complex compound structures, then specificity is improved, but drug development complexity and cost increase
Solution Approach 1:
The patent achieves reliable USP30 inhibition by optimizing parameters of a relatively simple bicyclic core structure. By varying substituents (R1-R6) at different positions and configurations, high inhibition efficacy is obtained without requiring complex multi-ring or macrocyclic structures, thus maintaining drug development feasibility.
Solution Approach 2:
The compound structure is segmented into a simple core bicyclic framework with separate substituent regions (R1-R6). This segmentation allows the core structure to provide baseline USP30 binding while substituents fine-tune selectivity and efficacy, achieving high reliability without overall structural complexity.
3Adaptability or versatility
If general DUB inhibition is achieved, then broad disease coverage is possible, but off-target effects on other cysteine proteases occur
Solution Approach 1:
The patent uses local quality by placing specific substituents at particular positions on the bicyclic core that create localized molecular recognition features. These localized features enable selective binding to USP30's active site while avoiding interaction with other cysteine proteases, thus eliminating off-target effects while maintaining therapeutic versatility.
Solution Approach 2:
The bicyclic core structure with specific substituents acts as an intermediary that selectively mediates inhibition of USP30. The molecular structure serves as a precise mediator that recognizes USP30's unique features, preventing off-target effects on other proteases while still providing broad therapeutic benefits for USP30-related diseases.
Data Source
AI summary
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.