S-enantiomers of beta-hydroxybutyrate and butanediol and methods for using same
Inventors
Verdin, Eric • Newman, John C.
Assignees
J David Gladstone Institutes • Buck Institute for Research on Aging • University of California San Diego UCSD
Publication Number
US-11773051-B2
Publication Date
2023-10-03
Expiration Date
2038-07-19
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Abstract
In various embodiments a compound comprising the enantiomerically enriched S-isomer S-BHB-S-1,3-butanediol is provided along with methods of use thereof.
Core Innovation
The invention provides compositions and methods involving the S enantiomer of beta-hydroxybutyrate (S-BHB), including a novel compound S-BHB-S-1,3-butanediol, which retains the natural signaling activities observed for the R-enantiomer but offers improved pharmacokinetics, particularly substantially improved serum half-life. This allows for effective administration of S-BHB or its related compounds to subjects, such as humans or non-human mammals.
The problem addressed is that ketogenic diets, which elevate ketone bodies like R-BHB, are used to treat various disorders including epilepsy and dementia but are difficult to maintain due to unpalatability and side effects. Additionally, while R-BHB acts as an energy currency and signaling molecule, it is rapidly metabolized. The invention identifies that the S-enantiomer of BHB maintains signaling functions and improves upon the pharmacokinetic limitations of R-BHB, providing new therapeutic opportunities.
Claims Coverage
The patent includes 14 independent claims focusing on methods of treatment using compositions enriched with the S-BHB-S-1,3-butanediol enantiomer and related formulations. The main inventive features cover therapeutic methods for a wide range of diseases and conditions and compositions enriched for the S-enantiomer.
Methods of treating neurocognitive disorders with S-BHB-S-1,3-butanediol compositions
Methods of treating dementia or other neurocognitive disorders by administering compositions comprising betahydroxybutyrate-1,3-butanediol enriched for the enantiomer S-BHB-S-1,3-butanediol.
Methods to prevent or delay onset of pre-Alzheimer's conditions and cognitive dysfunction
Methods comprising administration of compositions enriched for S-BHB-S-1,3-butanediol to prevent or delay onset or progression of pre-Alzheimer's conditions to Alzheimer's disease and to ameliorate symptoms.
Methods to reduce epileptiform brain activity using S-BHB-S-1,3-butanediol compositions
Administration of effective amounts of S-BHB-S-1,3-butanediol enriched compositions to reduce epileptiform activity in the subject's brain.
Methods to treat a broad spectrum of diseases with S-BHB-S-1,3-butanediol compositions
Methods for treating diseases including epilepsy, Parkinson's disease, heart failure, stroke, diabetic neuropathy, cancers, and others through administering compositions enriched for S-BHB-S-1,3-butanediol.
Methods for treating conditions related to elevated plasma free fatty acids
Administering effective amounts of compositions enriched with S-BHB-S-1,3-butanediol to treat conditions caused by or associated with elevated plasma free fatty acids.
Methods for treating conditions implicating weight changes with S-BHB-S-1,3-butanediol
Administering compositions enriched for S-BHB-S-1,3-butanediol to treat conditions where weight loss or gain is implicated, including suppressing appetite and treating obesity.
Methods for treating cognitive dysfunction, neurodegenerative diseases, muscle impairment, and fatigue
Administration of compositions enriched with S-BHB-S-1,3-butanediol to treat or prevent cognitive dysfunction, neurodegenerative disorders, muscle impairment, and fatigue.
Methods for treating metabolic and geriatric conditions with S-BHB-S-1,3-butanediol compositions
Administering compositions enriched for S-BHB-S-1,3-butanediol to treat diabetes, hyperthyroidism, metabolic syndrome X, and geriatric patients.
Methods for reducing effects of neurodegeneration, free radical toxicity, hypoxia, and hyperglycemia
Administering effective amounts of compositions enriched with S-BHB-S-1,3-butanediol to prevent or reduce effects of neurodegeneration, toxicity, hypoxic conditions, or hyperglycemia.
Methods for treating neurodegenerative diseases and disorders
Treatment methods for diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, epilepsy, glioblastoma and Huntington's chorea by administering compositions enriched for S-BHB-S-1,3-butanediol.
Methods for promoting alertness or improving cognitive function
Administering effective amounts of S-BHB-S-1,3-butanediol enriched compositions to promote alertness or improve cognitive function in a subject.
High enantiomeric purity of S-BHB-S-1,3-butanediol compositions
Compositions wherein the S-BHB-S-1,3-butanediol enantiomer comprises at least about 90%, preferably at least about 95%, and up to about 99% of the betahydroxybutyrate-1,3-butanediol.
The claims collectively cover methods of treating a wide range of neurological, metabolic, and degenerative conditions using compositions comprising betahydroxybutyrate-1,3-butanediol enriched for the S-BHB-S-1,3-butanediol enantiomer with high enantiomeric purity, emphasizing therapeutic uses, composition formulation, and efficacy in various clinical contexts.
Stated Advantages
The S-enantiomer of beta-hydroxybutyrate retains the natural signaling activities of the R-enantiomer while providing improved pharmacokinetics such as substantially improved serum half-life.
S-BHB is an effective inhibitor of histone deacetylase (HDAC) activity and may provide more sustained inhibition compared to R-BHB due to slower metabolism.
The compounds reduce plasma levels of free fatty acids and act on appetite centers in the brain to suppress appetite and promote weight loss or maintenance of healthy weight.
The S-enantiomers increase brain metabolic efficiency and elevate levels of neuropeptides (e.g., BDNF and CART) that promote neuronal growth, inhibit neurodegeneration, and improve cognitive function and alertness.
Documented Applications
Treatment of dementia, mild cognitive impairment, Alzheimer's disease, and prevention or delay of progression of pre-Alzheimer's cognitive dysfunction.
Reduction of epileptiform activity in the brain.
Treatment of neurological and degenerative diseases including epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis.
Treatment of conditions associated with elevated plasma free fatty acids and metabolic diseases such as diabetes, metabolic syndrome X, and hyperthyroidism.
Treatment of obesity, appetite suppression, and weight management.
Use as pharmaceutical formulations, dietary supplements, nutraceuticals, and incorporation into food products and beverages.
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