Piperazine Cyclic Ureas for Metabolically Stable RIP1 Kinase Inhibition
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Solution Overview
Problem
Current treatments for necroptosis and ferroptosis lack effective inhibitors with sufficient metabolic stability to target RIP1 kinase, leading to challenges in managing related pathological conditions and immunotherapy resistance.
Innovation Solution
Development of piperazine cyclic urea compounds that inhibit RIP1 kinase, offering exceptional metabolic stability and providing prodrugs that are hydrolyzed in the gut or blood to yield active inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for necroptosis and ferroptosis are used, then they can address some pathological conditions, but they lack effective inhibitors with sufficient metabolic stability to target RIP1 kinase
Solution Approach 1:
The patent modifies chemical parameters of the inhibitor molecules by introducing deuterium atoms (isotopic substitution) and optimizing molecular structure (formula I compounds with specific R1, R2, R3 substituents). This changes the metabolic parameters of the compounds, resulting in enhanced metabolic stability while maintaining their ability to inhibit RIP1 kinase effectively
Solution Approach 2:
The invention creates composite molecular structures combining piperazine cyclic urea cores with various aromatic substituents (R1, R2, R3 groups). These composite structures integrate multiple functional elements that work together to achieve both high metabolic stability and potent RIP1 kinase inhibition, as evidenced by the multiple compound examples provided
2Reliability
If RIP1 kinase inhibition is achieved, then necroptosis and ferroptosis are inhibited, but metabolic stability is insufficient with current compounds
Solution Approach 1:
The patent employs isotopic parameter changes (deuterium substitution) and structural parameter optimization to enhance metabolic stability. This allows the compounds to maintain their therapeutic effect of inhibiting pathological cell death (necroptosis and ferroptosis) while achieving the previously unattained metabolic stability required for effective treatment
3Ease of operation
If prodrugs are developed that are hydrolyzed in the gut or blood, then active inhibitors are yielded, but metabolic stability challenges remain
Solution Approach 1:
The patent designs prodrugs with preliminary hydrolyzable groups that convert to active inhibitors in vivo. The deuterated and structurally optimized core structures ensure that even after prodrug activation through hydrolysis in the gut or blood, the resulting active inhibitors maintain exceptional metabolic stability, thus resolving the contradiction between prodrug design and metabolic stability
Solution Approach 2:
By changing the metabolic parameters of the core inhibitor structure through deuterium substitution and aromatic substituent optimization, the patent ensures that the active inhibitors released from prodrugs maintain high metabolic stability, addressing the reliability concern while preserving the ease of prodrug activation
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 compounds demonstrate unexpectedly high metabolic stability, effectively inhibiting necroptosis and ferroptosis, addressing immunotherapy resistance and enhancing tumor immunity by targeting RIP1 kinase.
Implementation Method 1
prodrugs thereof, which are hydrolyzed, typically in the gut or blood, to yield the corresponding inhibitors
Data Source
AI summary
Provided are piperazine cyclic urea compounds that inhibit cellular necrosis and/or human receptor interacting protein 1 kinase (RIP1), pharmaceutically acceptable salts, hydrates and stereoisomers thereof. Provided are also pharmaceutical compositions, methods of making, and methods of use which include treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant improvement in the person's health or condition.