NLRP3 Inhibitor Compounds With P-gp-Mediated Peripheral Preference
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current NLRP3 inhibitors have limitations in pharmacological and physiological properties, and there is a need for compounds that minimize brain exposure while maintaining systemic distribution, particularly for treating peripheral indications, and reducing phospholipidosis risk.
Innovation Solution
Development of novel compounds of formula I with specific structural features that enhance efflux through P-gp transporters and reduce passive permeability, achieving peripheral preference and improved pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NLRP3 inhibitors are designed to maintain systemic distribution, then therapeutic efficacy is improved, but brain exposure increases leading to potential side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features (carboxylic acid group, specific pKa values between 3-5) that create differential distribution patterns. These structural characteristics enable the compounds to be retained in peripheral tissues while being actively transported out of the brain by P-gp, thus achieving different concentrations in different body compartments for the same compound.
Solution Approach 2:
The patent utilizes P-gp (P-glycoprotein) as an intermediary mechanism to control brain exposure. By designing compounds that are substrates for P-gp transport, the patent leverages this efflux transporter to actively pump the inhibitor out of the brain, thereby minimizing central nervous system exposure while maintaining peripheral therapeutic levels.
2Object-affected harmful factors
If compounds are designed to enhance peripheral preference, then brain exposure is reduced, but systemic distribution may be compromised
Solution Approach 1:
The patent applies parameter changes by optimizing specific molecular parameters including pKa values (3-5), molecular weight (250-400 Da), and the presence of a carboxylic acid group. These parameter adjustments create a balance where the compound is sufficiently lipophilic to distribute systemically but has specific characteristics that trigger P-gp mediated efflux from the brain, achieving the desired peripheral preference without compromising overall systemic availability.
3Duration of action of stationary object
If NLRP3 inhibitors are used for chronic treatment, then therapeutic benefit is improved, but phospholipidosis risk increases
Solution Approach 1:
The patent applies parameter changes by carefully controlling molecular properties including molecular weight (250-400 Da), logP values (1.5-3.5), and pKa (3-5). These parameter optimizations reduce the compound's affinity for cellular phospholipids while maintaining NLRP3 inhibitory activity, thereby minimizing phospholipidosis accumulation during chronic administration.
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 of formula I demonstrate reduced brain exposure, enhanced peripheral efficacy, and lower phospholipidosis risk, providing a more effective and safer treatment for NLRP3-related diseases.
Implementation Method 1
compounds that minimize brain exposure while maintaining systemic distribution, particularly for treating peripheral indications
Data Source
AI summary
The invention relates to novel compounds having the general formula Iwherein R1, R2, R9, A1, Rx and Ry are as described herein, composition including the compounds and methods of using the compounds.