Tocopheryl Quinone Derivatives for Lysosomal Storage Disorders
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Solution Overview
Problem
Current treatments for Lysosomal Storage Disorders (LSDs) and mitochondrial dysfunction lack effective pharmaceutical agents to significantly improve symptoms and prognosis, with existing therapies providing only limited abatement of symptoms and no cure.
Innovation Solution
Development of novel tocopheryl quinone derivatives with side chain modifications that enhance pharmacokinetics, combined with cyclodextrins, to reduce lysosomal substrate accumulation, restore mitochondrial function, and improve lysosomal and mitochondrial health, thereby treating LSDs and associated mitochondrial disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional tocopherols are used as lipid antioxidants, then membrane lipid composition is maintained, but they cannot effectively treat lysosomal storage disorders or improve mitochondrial function
Solution Approach 1:
The patent applies universality by designing tocopherol and tocopheryl quinone derivatives that simultaneously perform multiple functions: they act as lipid antioxidants maintaining membrane integrity, correct lysosomal storage disorders by reducing substrate accumulation, and improve mitochondrial function by enhancing ATP production. This multi-functional approach allows a single compound to address multiple aspects of LSD pathology without requiring separate therapies for each function.
Solution Approach 2:
The patent employs parameter changes by systematically modifying the chemical structure of tocopherols through side chain modifications (varying length, saturation, and substitution patterns) and oxidation states (tocopherol vs. tocopheryl quinone). These structural parameter changes result in compounds with optimized pharmacokinetic properties including improved metabolic stability, enhanced membrane permeability, and altered subcellular localization, enabling effective treatment of LSDs while maintaining antioxidant function.
2Reliability
If enzyme replacement therapy is used for LSDs, then symptom progression is slowed, but there is no cure and results are limited
Solution Approach 1:
The patent applies the intermediary principle by using tocopherol derivatives as mediator compounds that facilitate the correction of lysosomal storage disorders through indirect mechanisms. Rather than replacing the defective enzyme directly, these compounds act as intermediaries that modulate cellular processes, reduce substrate accumulation, and improve overall lysosomal and mitochondrial function. This intermediary approach provides broader therapeutic benefits beyond simple enzyme replacement.
Solution Approach 2:
The patent employs parameter changes by developing compounds with optimized pharmacokinetic parameters including enhanced metabolic stability, improved bioavailability, and targeted subcellular distribution. These parameter optimizations enable the compounds to achieve and maintain effective concentrations in lysosomes and mitochondria, providing sustained therapeutic efficacy that overcomes the limitations of current enzyme replacement therapies.
3Stability of the object's composition
If tocopheryl quinones are used to compete with Ubiquinione, then mitochondrial electron transport is inhibited, but metabolic stability is improved
Solution Approach 1:
The patent applies local quality by designing tocopheryl quinone derivatives with specific structural modifications that create localized functional differences. The side chain modifications (varying length, saturation, and substitution) create compounds with differential affinities for mitochondrial components. This allows certain derivatives to exhibit reduced mitochondrial decoupling activity while maintaining improved metabolic stability, effectively separating the stabilizing effect from the harmful mitochondrial inhibition.
Solution Approach 2:
The patent employs parameter changes by systematically varying the oxidation state and side chain parameters of tocopherol derivatives. By comparing tocopherol (reduced form) with tocopheryl quinone (oxidized form) and their various derivatives, the patent identifies compounds that optimize the balance between metabolic stability and mitochondrial function. Specific parameter adjustments in side chain structure reduce the mitochondrial decoupling effect while preserving the metabolic stability benefits.
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 novel derivatives demonstrate improved pharmacokinetics, reduced substrate accumulation, enhanced lysosomal function, and improved mitochondrial ATP production, leading to reduced pathological changes and increased efficacy with reduced side effects when used in combination with cyclodextrins.
Implementation Method 1
Tocopheryl quinones act as poor mitochondrial decouplers, because they compete with Ubiquinione, inhibiting the transference of electrons between complex III and complex I and complex II
Implementation Method 2
The compounds and compositions of the subject invention can, for example, be used to reduce substrate accumulation in several LSDs
Implementation Method 3
When the subject compounds are used in combination with a cyclodextrin, the solubility of the subject compounds in aqueous mixtures or solutions is improved
Implementation Method 4
The subject compounds and compositions, in a number of embodiments, can be used with cyclodextrins which will improve efficacy; in some cases, such improvement may be synergistic
Data Source
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AI summary
The subject invention relates to improved tocopheryl quinone derivatives and tocopherol derivatives having improved pharmacokinetics in vivo that can, in some embodiments, be useful in the treatment of Lysosomal Storage Disorders, restoration of normal mitochondrial ATP production, modulation of intracellular calcium ion concentration and other treatments or therapies. The tocopheryl quinone derivatives and tocopherol derivatives have side chains that have terminally halogenated carbon atoms.