NLRP3 Inflammasome Modulators With Oral Bioavailability and Potency
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Solution Overview
Problem
Current treatments for NLRP3-related diseases, such as Alzheimer's disease and gout, are limited by the bioavailability of biologics targeting IL-1 and small molecules with promiscuous modes of action and limited potency, necessitating the development of specific NLRP3 inflammasome pathway inhibitors with improved pharmacological and physiological properties.
Innovation Solution
Development of novel dihydrooxazole and thiourea or urea derivatives that modulate the NLRP3 inflammasome pathway, specifically inhibiting its activation and reducing IL-1 beta and/or IL-18 levels, thereby treating diseases responsive to NLRP3 inflammasome modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If biologics targeting IL-1 are used to treat NLRP3-related diseases, then anti-inflammatory effect is achieved, but bioavailability is limited
Solution Approach 1:
The patent replaces biologics (large protein molecules) with small molecule compounds that can orally bioavailable. The small molecules of formula (I) and (II) substitute for injectable biologics, transitioning from a mechanical/administrative system requiring injection to an oral pharmaceutical system that is easier to administer and has better bioavailability.
Solution Approach 2:
The patent changes the molecular parameters from large biologics to small molecules with specific molecular weight, lipophilicity, and structural characteristics (formula (I) and (II)) that enable oral absorption. This parameter change transforms the drug delivery system from one with limited bioavailability to one with improved oral bioavailability while maintaining therapeutic efficacy.
2Ease of operation
If small molecules are used to treat NLRP3-related diseases, then oral bioavailability is improved, but mode of action is promiscuous and potency is limited
Solution Approach 1:
The patent applies local quality by designing small molecules with specific structural features (formula (I) and (II)) that target the NLRP3 inflammasome pathway specifically. The molecules have particular substituent patterns, molecular weights, and structural characteristics that confer specificity for NLRP3 inhibition rather than promiscuous binding to multiple targets, thereby improving both potency and selectivity.
Solution Approach 2:
The patent creates a universal small molecule platform (formula (I) and (II)) that can treat multiple NLRP3-related diseases including Alzheimer's disease, non-alcoholic fatty liver disease, and gout. The molecules possess multi-functional properties by simultaneously achieving oral bioavailability, potent NLRP3 inhibition, and applicability across different disease indications, resolving the limitation of promiscuous but weak small molecules.
3Ease of operation
If current small molecule treatments are used, then oral administration is possible, but potency is limited
Solution Approach 1:
The patent optimizes molecular parameters including molecular weight (150-500 Da), lipophilicity (logP 1-5), and structural characteristics to achieve both oral bioavailability and high potency. The small molecules of formula (I) and (II) are designed with specific substituent patterns and molecular properties that enhance binding affinity to the NLRP3 inflammasome, thereby increasing potency while maintaining oral administration capability.
Data Source
Figure 1
AI summary
The invention relates to novel compounds of formulae (I') and (II') for the treatment, alleviation or prevention of diseases, disorders and abnormalities which are responsive to the modulation or inhibition of the activation of a component of the NLRP3 inflammasome pathway. In particular, the component of the inflammasome pathway is a NOD- like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the capability to modulate the NLRP3 inflammasome pathway. Further, the compounds of the present invention are suitable for the treatment, alleviation or prevention of diseases, disorders and abnormalities which are responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.