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-9663485-B2
Publication Date
2017-05-30
Expiration Date
2033-11-14
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Abstract
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.
Core Innovation
The invention relates to novel tocopheryl quinone derivatives and tocopherol derivatives having improved pharmacokinetics in vivo, which can be useful in the treatment of Lysosomal Storage Disorders (LSDs), diseases caused by mitochondrial dysfunction, restoration of normal mitochondrial ATP production, and modulation of intracellular calcium ion concentrations. The derivatives include side chains terminally halogenated, typically with tri-halogenated methyl groups, which confer metabolic stability and improved pharmacokinetic properties such as CNS penetration and enhanced exposure.
The problem being addressed is that LSDs are rare inherited diseases caused by lysosomal enzyme failure, leading to accumulation of substrates such as lipids and glycoproteins in lysosomes, resulting in diverse severe symptoms and often fatal outcomes. Current therapies, including enzyme replacement therapy and substrate reduction, provide limited symptomatic relief. There is a clear need for improved pharmaceutical agents that can reduce lysosomal substrate accumulation, restore lysosomal and mitochondrial function, and improve overall disease outcomes.
The compounds of the invention, including tocopheryl quinone and tocopherol derivatives with terminal halogenation on the side chain, reduce cholesterol and substrate accumulation in LSD cells, restore normal lysosomal size, modulate intracellular calcium levels, improve mitochondrial ATP production, and exhibit improved pharmacokinetics compared to prior art. When combined with cyclodextrins, these compounds synergistically enhance lysosomal function and solubility, allowing dose reduction and potential mitigation of side effects. These features address limitations of prior treatments and provide improved therapeutic options for LSDs and mitochondrial disorders.
Claims Coverage
The patent includes five independent claims covering compounds of four distinct structural formulas and methods of treatment using these compounds and compositions comprising them.
Compounds with terminally halogenated side chains
The invention claims compounds of formula I through IV, where the side chains are alkyl, alkenyl, or alkynyl, straight or branched, modified with terminal tri-halogenated methyl groups (halogens at the terminal carbon), conferring metabolic stability and improved pharmacokinetics by resisting oxidation and hydrolysis.
Pharmaceutical compositions comprising the claimed compounds
Pharmaceutical compositions comprising one or more of the claimed compounds along with pharmaceutically acceptable excipients or vehicles are claimed, which may optionally include cyclodextrins to improve solubility and therapeutic efficacy.
Method of treating lysosomal storage disorders
Methods of treating lysosomal storage disorders by administering therapeutically effective amounts of the claimed pharmaceutical compositions to patients in need, optionally with co-administration of cyclodextrins to further enhance efficacy.
Method for improving mitochondrial ATP production
Methods for improving mitochondrial ATP production by contacting mitochondria with any of the compounds of formulas I-IV, thereby increasing Ca2+ influx and cholesterol exocytosis in patient cells, addressing mitochondrial dysfunction associated with LSDs and related diseases.
Overall, the claims cover novel terminally halogenated tocopheryl quinone and tocopherol derivatives, their pharmaceutical compositions, and methods of treating LSDs and enhancing mitochondrial function, emphasizing improved pharmacokinetics, metabolic stability, and synergistic combination with cyclodextrins.
Stated Advantages
Reduction of lysosomal substrate accumulation and cholesterol in LSD cells.
Improved lysosomal size normalization and function.
Modulation of intracellular calcium ion concentrations.
Restoration and improvement of mitochondrial ATP production and function.
Improved pharmacokinetics including increased metabolic stability and enhanced central nervous system penetration.
Synergistic effects when combined with cyclodextrins, leading to improved solubility and efficacy and allowing dose reduction to minimize side effects.
Documented Applications
Treatment of Lysosomal Storage Disorders such as Niemann Pick Type C (NPC), Wolman, Niemann Pick Type A, Farber, Tay-Sachs, MSIIIB, and CLN2 (Batten) diseases.
Treatment of mitochondrial disorders including Friedreich's ataxia, Kearns-Sayre syndrome (KSS), Myoclonus epilepsy with ragged-red fibers (MERRF), MELAS, Leber hereditary optic neuropathy (LHON), Leigh syndrome, MNGIE, Pearson syndrome, and NARP.
Use in neurodegeneration related to LSDs and mitochondrial dysfunction.
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