Monomethyl Fumarate Prodrugs for Sustained Release and Lower Side Effects
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Solution Overview
Problem
Current fumaric acid esters, such as dimethyl fumarate, suffer from significant drawbacks including high interpatient variability in drug absorption, reduced bioavailability due to food effects, frequent dosing requirements, and severe side effects like flushing and gastrointestinal issues, making long-term therapy challenging.
Innovation Solution
Development of novel prodrugs, specifically aminoalkyl prodrugs of monomethyl fumarate, which provide sustained release formulations capable of maintaining a therapeutically effective level for at least 8 to 24 hours, reducing side effects, and improving physical stability and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dimethyl fumarate is used for treatment, then therapeutic effect is achieved, but dosing frequency must be high and patient compliance deteriorates
Solution Approach 1:
The patent segments the rapid absorption and elimination phases into distinct components by using prodrug structures that control the timing and rate of active drug release, thereby extending therapeutic effect duration without requiring frequent dosing
Solution Approach 2:
The prodrug structures are designed to undergo preliminary metabolic conversion in the body before releasing the active fumarate compound, allowing sustained release over 24 hours or longer and reducing dosing frequency while maintaining therapeutic efficacy
2Reliability
If dimethyl fumarate is administered, then therapeutic benefit is obtained, but side effects increase
Solution Approach 1:
The prodrug acts as an intermediary compound that is converted metabolically to the active fumarate, allowing controlled release that reduces peak plasma concentrations and associated side effects like flushing and gastrointestinal disturbances while maintaining therapeutic benefit
Solution Approach 2:
The prodrug structure provides a buffering effect by controlling the rate of active drug release, cushioning against sudden high concentrations that cause side effects while ensuring sufficient drug levels for therapeutic effect
3Reliability
If fumaric acid esters are used, then treatment efficacy is achieved, but bioavailability decreases due to food effects
Solution Approach 1:
The patent changes the chemical parameters of the fumarate compound by creating prodrug derivatives with modified physicochemical properties that are less susceptible to food-effect variability, thereby improving and stabilizing bioavailability while maintaining treatment efficacy
4Reliability
If dimethyl fumarate is administered, then therapeutic effect is achieved, but dosing complexity increases
Solution Approach 1:
The sustained-release prodrug formulation performs the drug release function over an extended period (24 hours or longer) through preliminary metabolic conversion, eliminating the need for multiple daily doses and associated monitoring, thereby reducing dosing complexity while maintaining therapeutic effect
Data Source
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AI summary
The present invention provides compounds of formula (I), and pharmaceutical compositions thereof.