Small-Molecule NLRP3 Inflammasome Inhibitors With Improved Solubility
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Solution Overview
Problem
There is a need for small-molecule synthetic inhibitors of the NLRP3 inflammasome that exhibit improved inhibition, favorable toxicological profiles, and advantageous physical properties compared to existing inhibitors, as no such compounds have been approved for medical use, and existing inhibitors may have limitations in efficacy and safety.
Innovation Solution
Development of compounds of Formula (I) or their pharmaceutically acceptable salts, which act as potent inhibitors of the NLRP3 inflammasome, potentially offering improved inhibition, reduced hERG inhibition, favorable pharmacokinetic profiles, and higher aqueous solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing NLRP3 inflammasome inhibitors are used, then some inhibition effect is achieved, but the inhibition efficacy is insufficient and toxicological profiles are unfavorable
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures (Formula I with various R1-R6 substituents) to optimize the balance between inhibition efficacy and toxicological profile. The compounds achieve improved NLRP3 inhibition while reducing hERG inhibition and improving pharmacokinetic properties through structural parameter optimization.
Solution Approach 2:
The patent employs composite molecular structures combining multiple functional groups and scaffolds (phthalazin, pyrido[3,4-d]pyridazin, cyclohexyl, fluorinated phenyl groups) to create compounds with enhanced NLRP3 inhibition while maintaining favorable safety profiles and pharmacokinetic characteristics.
2Reliability
If existing NLRP3 inflammasome inhibitors are used, then some therapeutic effect is achieved, but aqueous solubility is insufficient
Solution Approach 1:
The patent improves aqueous solubility through parameter changes including introduction of polar groups (hydroxyl, carboxyl), ionic groups (carboxylic acid salts), and fluorinated substituents that enhance water solubility while maintaining NLRP3 inhibition activity and therapeutic efficacy.
Data Source
AI summary
The specification generally relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, where R1, R2A, R2B, R2C, R2D, W, X, Y, and Z have the meanings defined herein. Such compounds are useful in inhibiting NLRP3 inflammasome activity and may be useful as therapeutic agents. The specification also relates to the use of such compounds to treat or prevent diseases and conditions in which the NLRP3 inflammasome is implicated. The specification further relates to compositions comprising such compounds.