Urea NLRP3 Inhibitors for Controlled Inflammasome Modulation
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Solution Overview
Problem
There is an unmet need for small molecules that can modulate NLRP3 activity to treat various inflammatory and degenerative diseases, as NLRP3 hyperactivation is linked to conditions such as NASH, atherosclerosis, Alzheimer's disease, Parkinson's disease, diabetes, and autoinflammatory diseases.
Innovation Solution
Development of NLRP3 inhibitors of Formula (I-B) and their pharmaceutically acceptable salts and tautomers, which can be used in pharmaceutical compositions for treatment and prevention.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NLRP3 is activated to respond to pathogens and cellular stress, then immune defense is enhanced, but uncontrolled activation leads to chronic inflammation and tissue damage
Solution Approach 1:
The patent develops small molecule compounds that bind to NLRP3 and modulate its activity by changing its functional state. The compounds alter the activation threshold and duration of NLRP3, transforming it from a hyperactive state causing chronic inflammation to a controlled state that maintains protective immunity. This parameter modulation resolves the contradiction between effective immune response and prevention of pathological inflammation.
Solution Approach 2:
The invention creates a negative feedback mechanism where the small molecule compounds act as inhibitors that reduce NLRP3 activity when it becomes excessively activated. The compounds detect and respond to NLRP3 activation states, providing regulatory feedback that prevents uncontrolled inflammation while preserving the initial protective immune response. This feedback control resolves the contradiction by allowing appropriate activation while preventing harmful overactivation.
2Reliability
If small molecules are designed to inhibit NLRP3 activity, then treatment of inflammatory diseases is achieved, but selectivity and off-target effects become challenges
Solution Approach 1:
The patent employs structure-activity relationship analysis to optimize specific molecular regions of the small compounds that interact with NLRP3. By modifying local chemical properties and spatial arrangement of functional groups, the compounds achieve enhanced binding affinity and selectivity for NLRP3 while minimizing interactions with other proteins. This local optimization resolves the contradiction between effective inhibition and reduction of off-target effects.
Solution Approach 2:
The invention utilizes conformational dynamics and induced fit mechanisms where the small molecules adapt their structure upon binding to NLRP3. The compounds exhibit dynamic flexibility that allows optimal interaction with the NLRP3 binding pocket while maintaining selectivity. This dynamic adaptation enhances binding specificity and reduces off-target effects, resolving the contradiction between treatment efficacy and selectivity.
Data Source
AI summary
The present disclosure relates to compounds of Formula (I-B):and pharmaceutically acceptable salts and tautomers thereof, wherein Ring A, Ring B, R1, R2a, R2b, R3, R4, m, n, and p are described herein, and methods of preparation, methods of treatment and prevention, and pharmaceutical compositions comprising same. The present disclosure further relates to the use of the compounds of Formula (I-B), and pharmaceutically acceptable salts and tautomers thereof, in the treatment or prevention of NLRP3-related diseases and disorders.