Tocopherol and tocopheryl quinone derivatives as correctors of lysosomal storage disorders
Inventors
Marugan, Juan Jose • Zheng, Wei • Xiao, Jingbo • McKew, John
Assignees
US Department of Health and Human Services
Publication Number
US-10370348-B2
Publication Date
2019-08-06
Expiration Date
2033-11-14
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Abstract
The subject invention relates to improved tocopheryl quinine derivatives and tocopherol derivatives having improved pharmacokinetics in vivo that can, in some embodiments, be useful in the treatment of Lysosomal Storage Disorder, 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.
Core Innovation
The invention relates to novel tocopheryl quinone derivatives and tocopherol derivatives that have been modified to include terminally halogenated side chains, particularly tri-halogenated methyl groups. These modifications confer improved pharmacokinetics in vivo, including enhanced metabolic stability, reduced oxidation, and better brain penetration. The derivatives can modulate mitochondrial potential, intracellular calcium ion concentration, improve mitochondrial ATP production, and restore normal lysosomal function, which is beneficial in the treatment of Lysosomal Storage Disorders (LSDs) and mitochondrial dysfunction diseases.
LSDs are genetic disorders characterized by lysosomal enzymatic failure leading to the accumulation of substrates such as lipids, glycoproteins, and mucopolysaccharides, causing severe and often fatal symptoms including developmental delays and organ dysfunction. Existing therapies like enzyme replacement or substrate reduction have limited effects, and there remains an urgent need for effective pharmaceutical agents for LSD treatment. The invention addresses this need by synthesizing tocopheryl quinone and tocopherol derivatives that reduce lysosomal substrate accumulation, restore lysosomal size, and improve mitochondrial function, sometimes in synergistic combination with cyclodextrins to enhance efficacy and solubility.
Claims Coverage
The patent contains multiple independent claims that focus on tocopheryl quinone derivatives and tocopherol derivatives with specific side chain modifications and their pharmaceutical uses.
Tocopheryl quinone derivatives with terminally halogenated side chains
Compounds of tocopheryl quinone derivatives having side chains modified with terminal tri-halogenated methyl groups that improve pharmacokinetics by increasing metabolic stability and reducing oxidation, thereby enhancing brain penetration and therapeutic efficacy in LSD and mitochondrial dysfunction.
Pharmaceutical compositions comprising the modified tocopheryl quinone derivatives
Pharmaceutical compositions comprising the tocopheryl quinone derivatives with pharmaceutically acceptable vehicles, optionally combined with cyclodextrins to improve solubility and efficacy, for treating lysosomal storage disorders and related diseases.
Tocopherol derivatives with terminally halogenated side chains
Modified tocopherol derivatives bearing terminal tri-halogenated methyl groups on the side chain that exhibit improved lysosomal and mitochondrial function, pharmacokinetics, and synergistic effects when administered with cyclodextrins.
Pharmaceutical compositions comprising the tocopherol derivatives
Pharmaceutical compositions comprising the modified tocopherol derivatives and pharmaceutically acceptable vehicles, optionally including cyclodextrins, used to treat LSDs and associated deficiencies by restoring lysosomal function and improving mitochondrial ATP production.
The independent claims cover novel tocopheryl quinone and tocopherol derivatives modified with terminally halogenated side chains and their pharmaceutical compositions. These inventions provide improved pharmacokinetics, metabolic stability, enhanced efficacy in treating LSDs and mitochondrial disorders, and optionally synergistic effects when combined with cyclodextrins.
Stated Advantages
The compounds demonstrate reduced substrate accumulation in LSD cells and reduced pathological changes observable by electron microscopy.
They modulate intracellular calcium concentration and improve mitochondrial function, including ATP production.
Improved pharmacokinetics, including enhanced metabolic stability and increased central nervous system penetration leading to better exposure in brain tissues.
Increased lipophilicity improves membrane fluidity, thereby restoring lipid homeostasis and normal lysosomal size.
Combination with cyclodextrins improves solubility and efficacy, producing a synergistic effect and allowing dose reduction to minimize side effects.
Documented Applications
Treatment of Lysosomal Storage Disorders including Niemann-Pick Type C, Tay-Sachs, mucopolysaccharidoses, and others.
Therapeutic use in diseases caused by mitochondrial dysfunction, such as Friedreich's ataxia and other mitochondrial cytopathies.
Restoration of normal mitochondrial ATP production and modulation of intracellular calcium ion concentration.
Use in combination with cyclodextrins to enhance lysosomal function and cholesterol metabolism in LSD patients.
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