α,β-Unsaturated Methacrylic Esters for Metabolic Stability
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Solution Overview
Problem
Current anti-inflammatory agents, such as dimethyl fumarate, exhibit systemic exposure issues and lose efficacy due to hydrolysis, while existing itaconate derivatives like 4-octyl itaconate have limited reactivity and metabolic stability, necessitating the development of new α,β-unsaturated carboxyl compounds with enhanced properties.
Innovation Solution
Development of α,β-unsaturated methacrylic esters with heteroaryl groups that effectively reduce cytokine release and activate NRF2 in cells, offering improved metabolic stability and anti-inflammatory effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dimethyl fumarate is used as an anti-inflammatory agent, then anti-inflammatory effects are achieved, but systemic exposure is lost due to hydrolysis in vivo
Solution Approach 1:
The patent modifies the chemical structure of fumarate derivatives by introducing heteroaryl groups and varying ester substitutions to create compounds with improved metabolic stability while maintaining anti-inflammatory activity. This structural parameter change prevents hydrolysis-induced loss of efficacy
Solution Approach 2:
The invention combines heteroaryl moieties with methacrylic ester structures to create hybrid molecules that exhibit both improved metabolic stability and anti-inflammatory properties. These composite structures resist hydrolysis while maintaining biological activity
2Reliability
If itaconate derivatives like 4-octyl itaconate are used, then some anti-inflammatory activity is achieved, but reactivity and metabolic stability are limited
Solution Approach 1:
The patent modifies itaconate derivative structures by introducing heteroaryl groups and adjusting ester substitutions to enhance chemical reactivity and metabolic stability simultaneously, creating more versatile anti-inflammatory agents
3Power
If glucocorticoids are used for acute inflammatory flares, then powerful anti-inflammatory effects are achieved, but unwanted side-effects and resistance develop with longer term use
Solution Approach 1:
The patent develops novel methacrylic ester compounds that act as intermediary substances with intermediate potency between NSAIDs and glucocorticoids, providing effective anti-inflammatory action with reduced side-effect profile and lower risk of resistance development
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
These compounds demonstrate enhanced anti-inflammatory properties by reducing cytokine release and activating NRF2, potentially outperforming 4-octyl itaconate in terms of efficacy and metabolic stability.
Implementation Method 1
reaction of the electrophilic α,β-unsaturated ester moiety with nucleophilic cysteine residues on kelch-like ECH-associated protein 1 (KEAP1)
Implementation Method 2
These compounds demonstrate enhanced anti-inflammatory properties by reducing cytokine release and activating NRF2
Data Source
AI summary
The invention relates to compounds of formula (I):wherein A, RA1, RA2, RB, RC and RD are as defined herein, and associated aspects.