Metabolically Robust Eicosanoid Analogues for GDF-15 Reduction
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Solution Overview
Problem
Existing n-3 PUFA-derived CYP metabolites, such as 17,18-EEQ and 19,20-EDP, are not used as therapeutics due to limited bioavailability and chemical instability, and GDF-15 is a marker associated with adverse cardiovascular and metabolic conditions, necessitating a therapeutic approach to lower its levels.
Innovation Solution
Development of metabolically robust analogues of n-3 PUFA metabolites, represented by compounds of general formula (I), which are designed to modulate GDF-15 plasma concentration and treat associated disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If n-3 PUFA-derived CYP metabolites (17,18-EEQ and 19,20-EDP) are used as therapeutics, then GDF-15 levels can be lowered, but their limited bioavailability and chemical instability prevent effective treatment
Solution Approach 1:
The patent modifies the chemical structure of n-3 PUFA metabolites by changing parameters such as introducing fluorine atoms at specific positions (e.g., 14-fluoro, 17-fluoro), adjusting double bond configurations, and modifying side chain structures. These parameter changes enhance metabolic stability and chemical robustness while preserving the ability to lower GDF-15 levels, directly resolving the contradiction between therapeutic effectiveness and chemical stability
Solution Approach 2:
The invention creates composite molecular structures that combine the pharmacologically active core structure of n-3 PUFA metabolites with stabilizing modifications (fluorine substitution, cyclic structures, protected functional groups). This composite approach maintains the biological activity necessary for lowering GDF-15 while incorporating structural elements that improve chemical stability and metabolic resistance, thereby resolving the contradiction between reliability and stability
2Reliability
If n-3 PUFA-derived CYP metabolites are used as therapeutics, then GDF-15 levels can be lowered, but their limited bioavailability prevents effective treatment
Solution Approach 1:
The patent employs parameter changes including deuterium substitution at metabolically labile positions, introduction of fluorine atoms to block metabolic oxidation sites, and modification of hydroxyl groups to ethers or esters. These changes reduce metabolic clearance and improve oral bioavailability while maintaining the pharmacological activity to lower GDF-15, directly addressing the contradiction between therapeutic effectiveness and bioavailability
Solution Approach 2:
The invention performs preliminary protective modifications on the n-3 PUFA metabolite structure before administration, such as forming stable esters, ethers, or amides that protect against premature metabolism. These preliminary actions ensure the compound reaches systemic circulation in sufficient quantities (improved bioavailability) while retaining the ability to lower GDF-15 levels, resolving the contradiction between reliability and quantity of substance
Data Source
AI summary
The present invention relates to compounds according to general formula (I) which are metabolically robust analogues of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs) for use in treating, reducing the risk of developing or preventing a disorder associated with an elevated GDF-15 plasma concentration.