WO2024036225A1 - Épicatéchine pour l'inhibition de la toxicité du glutamate - Google Patents

Épicatéchine pour l'inhibition de la toxicité du glutamate Download PDF

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Publication number
WO2024036225A1
WO2024036225A1 PCT/US2023/071953 US2023071953W WO2024036225A1 WO 2024036225 A1 WO2024036225 A1 WO 2024036225A1 US 2023071953 W US2023071953 W US 2023071953W WO 2024036225 A1 WO2024036225 A1 WO 2024036225A1
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epicatechin
disease
subject
administered
glutamate
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PCT/US2023/071953
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English (en)
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George F. Schreiner
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Epirium Bio Inc.
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Publication of WO2024036225A1 publication Critical patent/WO2024036225A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates in some aspects to treating or preventing a condition related to acute or chronic excessive glutamate exposure using epicatechin.
  • Glutamate is one of the most important excitatory neurotransmitters, and binds to a family of glutamate receptors.
  • glutamate levels in the extracellular fluid are too high, a subset of glutamate receptors, known as the N-methyl-D-aspartate (NMD A) receptors, become activated as calcium (Ca 2+ ) channels that let in excess quantities of Ca 2+ .
  • NMD A receptors permit the influx of Ca 2+ to the extent that it is toxic to mitochondria if glutamate activation of NMDA receptors is excessive.
  • High Ca 2+ impairs mitochondrial membrane potential, reducing the production of ATP and increasing hydrolysis of ATP by ATP synthase, thereby reducing availability of ATP required for cellular functioning.
  • Acute exposure Ca 2+ may cause several downstream effects, such as: (i) sustained activation of Ca 2+ activated enzymes such as calpain, caspases, and phospholipases, (ii) mitochondrial damage, via opening of the mitochondrial permeability transition pore (mPTP), and (iii) bioenergetic depletion of the central nervous system (CNS), ultimately resulting in loss of postsynaptic structures neuronal cell death and brain dysfunction.
  • sustained activation of Ca 2+ activated enzymes such as calpain, caspases, and phospholipases
  • mitochondrial damage via opening of the mitochondrial permeability transition pore (mPTP)
  • CNS central nervous system
  • Glutamate toxicity is implicated in several different acute CNS syndromes and in progressive neurodegeneration.
  • acute glutamate exposure is associated with both calcium (Ca 2+ ) overload of the neuron and accompanying mitochondrial injury and depletion.
  • Acute release of toxic levels of glutamate has been implicated in the neurological impairment associated with traumatic injury to the head and spinal cord, epilepsy, and stroke, among other acute neurological syndromes.
  • the release of glutamate into the extracellular space by damaged or dying neurons has been implicated as a progression factor in chronic neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS.
  • kits for treating or preventing diseases or disorders resulting from acute or chronic excessive glutamate exposure, excess calcium (Ca 2+ ) levels, and/or reactive oxygen species, using epicatechin are useful for the treatment of a variety of diseases or disorders, such as central nervous system (CNS) diseases or disorders and/or diseases or disorders associated with intracellular Ca 2+ buildup.
  • CNS central nervous system
  • One aspect of the present application provides a method of treating or preventing a condition related to acute or chronic excessive glutamate exposure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the glutamate exposure induces intracellular calcium (Ca 2+ ) buildup.
  • the condition is selected from the group consisting of status epilepticus, neuroinflammatory disorders, pediatric seizure disorders, neuronal exocitoxicity, over activation of the N-methyl-D-aspartate (NMDA) receptor, post-operative syndromes of cognition loss, and loss of synaptic density.
  • NMDA N-methyl-D-aspartate
  • ROS reactive oxygen species
  • a method of treating a condition related to acute or chronic exposure to intracellular calcium (Ca 2+ ) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the condition is neuronal exci totoxi city.
  • a method of lowering intracellular Ca 2+ levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the subject has a disease or disorder selected from the group consisting of spinal cord injury or abnormality, liver disease, kidney disease, impaired cognition, neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, cardiomyopathy, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease, exocrine pancreatic insufficiency, impaired wound healing, and growth of cancer cells.
  • the subject has a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • the epicatechin is administered in the form of a pharmaceutical composition comprising the epicatechin or the pharmaceutically acceptable salt, solvate, or co-crystal thereof, and a pharmaceutically acceptable excipient.
  • the epicatechin is in the form of a co-crystal.
  • the epicatechin is administered orally, sublingually, subcutaneously, parenterally, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarily, vaginally, rectally, or intraocularly. In some embodiments, the epicatechin is administered orally or intravenously.
  • the epicatechin is administered in the form of a tablet, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol.
  • the epicatechin is administered at a daily dosage of about 5 to about 500 mg. In some embodiments, the daily dosage is administered in a single dose or in 2, 3, or 4 divided doses. In some embodiments, the epicatechin is administered each day, every other day, weekly, every two weeks, every three weeks, or every four weeks.
  • the epicatechin is (+)-epicatechin. In some embodiments, the epicatechin is (-)-epicatechin. In some embodiments, the epicatechin comprises at least 75% (+)-epicatechin. In some embodiments, the epicatechin comprises at least 75% (-)- epicatechin.
  • the epicatechin is administered in combination with one or more additional therapeutic agents. In some embodiments, the epicatechin and the one or more additional therapeutic agents are administered concurrently. In some embodiments, the epicatechin and the one or more additional therapeutic agents are administered sequentially. [0021] Also provided are kits and articles of manufacture comprising any one of the compositions described above and instructions for any one of the methods described above.
  • FIGS. 1A-1E show the effects of EPM-01 (i.e., (+)-epicatechin; FIG. 1A), EPM-03 (z.e., (-)-epicatechin; FIG. IB), EPM-06 i.e., 11 -hydroxypregnenolone; FIG. 1C), EPM-07 i.e., 11- hydroxyprogesterone; FIG. ID), or catechin (FIG. IE) on NMDA-induced neurotoxicity. Values are expressed as percentage of control values and are from 4 independent experiments, each with 4-10 replicates per condition. **p ⁇ 0.01, ***p ⁇ 0.001, ****p ⁇ 0.0001
  • FIG. 2A shows an exemplary scheme of rat hippocampal circuitry.
  • FIG. 2B shows a representative transverse section of a rat hippocampal slice.
  • the closed circle shows the stimulating electrode, the large rectangle shows the recording electrodes for fESPS, and the small rectangle shows the recording electrodes for population spikes.
  • FIGS. 2C-2D show that EPM-01 i.e., (+)-epicatechin) improved fESPS recovery following NMDA activation (FIG. 2C) or oxygen-glucose deprivation (OGD) (FIG. 2D).
  • the statistics were performed using a two-way Anova with a Dunett’s multiple comparisons test. P -values were marked in the data presentations using the following notation: ns not significant, * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001, **** p ⁇ 0.0001.
  • FIGS. 3 A-3B show bodyweight (FIG. 3 A) and survival (FIG. 3B) of mice treated with EPM-01 (i.e., (+)-epicatechin).
  • FIGS. 4A-4C show weekly assessment of body condition score (FIG. 4A), clinical score (FIG. 4B), and neurological score (FIG. 4C) of R6/2 mice treated with EPM-01 (i.e., (+)-epicatechin).
  • EPM-01 i.e., (+)-epicatechin
  • FIGS. 5A-5D show activity chamber evaluations, including distance moved (FIG.
  • FIG. 6 shows rotarod evaluations of R6/2 mice treated with EPM-01 (z.e., (+)- epicatechin). Data represent average latency to fall across 3 trials performed on each of weeks 7, 9 and 11. **p ⁇ 0.01, ***p ⁇ 0.001, comparison of non-carrier-vehicle vs R6/2 hemi- vehicle Tukey’s post hoc comparison of means.
  • FIGS. 7A-7H show distance (FIG. 7A), velocity (FIG. 7B), active behavior duration (FIG. 7C), climbing (FIG. 7D), rearing (FIG. 7E), grooming (FIG. 7F), digging (FIG. 7G), and seizure duration (FIG 7H), of R6/2 mice treated with EPM-01 (z.e., (+)-epicatechin) during the novel cage observation test across weeks 6, 9, 12 and 13.
  • EPM-01 z.e., (+)-epicatechin
  • FIGS. 8A-8B show fear conditioning analysis of R6/2 mice treated with EPM-01 (z.e., (+)-epicatechin).
  • Line graphs indicate % Freezing during Day 1 training and Day 2 context for each group in FIG. 8A and 8B.
  • Described herein are methods of treating or preventing diseases or disorders resulting from acute or chronic excessive glutamate exposure, excess calcium (Ca 2+ ) levels, and/or reactive oxygen species, using epicatechin. Such methods are useful for the treatment of a variety of diseases or disorders, such as central nervous system (CNS) diseases or disorders and/or diseases or disorders associated with intracellular Ca 2+ buildup.
  • CNS central nervous system
  • the present application is based at least in part on the inventor’s finding decreasing Ca 2+ levels via treatment with epicatechin, can be used to boost mitochondrial function rather than blocking the glutamate receptor outright.
  • the novel mechanism of epicatechin preserves neuronal function in the setting of glutamate neurotoxicity, with clear therapeutic implications for a spectrum of central nervous system (CNS) disorders.
  • CNS diseases including seizure disorders, spinal cord injury, and neurodegeneration, may be amenable to epicatechin mitochondrial-targeted therapies, because of a shared mechanism of action unique to epicatechin.
  • the present application in one aspect provides a method of treating or preventing a condition related to acute or chronic excessive glutamate exposure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • terapéuticaally effective amount indicates an amount that results in a desired pharmacological and/or physiological effect for the condition.
  • the effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition.
  • the term “pharmaceutically acceptable excipient,” and cognates thereof, refers to adjuvants, binders, diluents, etc. known to the skilled artisan that are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more excipients are also contemplated.
  • the pharmaceutically acceptable excipient(s) and any additional components, as described herein, should be compatible for use in the intended route of administration (e.g., oral, parenteral) for a particular dosage form, as would be recognized by the skilled artisan.
  • co-crystal denotes crystalline molecular complexes, encompassing hydrates and solvates.
  • Co-crystals are composed of multi-component, stoichiometric and neutral molecular species, each existing as a solid under ambient conditions. Co-crystals exhibit properties different from free drugs or salts. The solid form influences relevant physico-chemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with superior properties.
  • treat is meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
  • beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • the present application provides methods of using epicatechin.
  • Epicatechin may boost mitochondrial function by increasing the availability of ATP, which can be used to pump excess calcium (Ca 2+ ) out of the cell or into internal storage compartments. Through normalization of Ca 2+ levels, toxic enzyme activation, and cell death can be prevented while preserving the normal and essential role of glutamate neurotransmission.
  • ATP ATP
  • Ca 2+ excess calcium
  • epicatechin preserves neuronal function in the setting of glutamate neurotoxicity, with clear therapeutic implications for a spectrum of CNS disorders.
  • Epicatechin is flavonoid that is a more active isomer of catechin.
  • Catechin is a flavan-3-ol, a type of natural phenol and antioxidant.
  • Epicatechin and catechin are abundant flavanols in fruits, chocolate, red wine, and tea.
  • a method comprising use of a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the term “epicatechin” as used herein refers to epicatechin in its various forms, including but not limited to epicatechin, a co-crystal of epicatechin, a therapeutically effective amount of epicatechin, a pharmaceutically acceptable salt of epicatechin, a pharmaceutical composition comprising epicatechin, or any combination thereof.
  • the epicatechin of the present disclosure may promote neuronal survival.
  • the epicatechin is neuroprotective.
  • the epicatechin increases neuronal survival at concentrations greater than about 0.1 pM, such greater than any of about 10 pM, 0.1 nM, 1 nM, 2 nM, 5 nM, 10 nM, or greater.
  • the epicatechin increases neuronal survival at concentrations less than about 10 nM, such as less than any of about 5 nM, 2 nM, 1 nM, 0.1 nM, 10 pM, 0.1 pM, or less.
  • the epicatechin is neuroprotective against CNS disease, metabolic disease, mitochondrial disease, or any combination thereof. In some embodiments, the epicatechin is neuroprotective against stroke, Parkinson’s disease, Huntington's disease, oxygen deprivation (e.g., cardiac ischemia), ischemic penumbra, seizure conditions, and spinal cord injury.
  • the epicatechin reduces the expression of anti-inflammatory markers.
  • the anti-inflammatory marker is IL-10, ILlb, or MCP.l
  • the epicatechin reduces seizures associated with disease.
  • the epicatechin reduces mortality in early phases of disease progression.
  • the epicatechin increases neuronal survival against NMDA toxicity (e.g., neuronal excitotoxicity). In some embodiments, the epicatechin promotes sustained neuronal recovery. In some embodiments, the epicatechin accelerates recovery of neuronal membrane potential during neuronal excitotoxicity. In some embodiments, the epicatechin increases ATP availability during neuronal excitotoxicity. In some embodiments, the increased ATP availability is used to pump Ca 2+ out of the neuron. In some embodiments, the increased ATP availability is used to pump Ca 2+ into intracellular stores (e.g., the endoplasmic reticulum). In some embodiments, the pumping of Ca 2+ prevents the activation of caspase. In some embodiments, the pumping of Ca 2+ prevents the opening of the mitochondrial permeability transition pore (mPTP).
  • mPTP mitochondrial permeability transition pore
  • the epicatechin stimulates an adaptive stress response. In some embodiments, the epicatechin promotes tissue regeneration.
  • epicatechin is enantiomerically pure or enantiomerically enriched. In some embodiments, the epicatechin is enantiomerically pure or enantiomerically enriched (+) epicatechin. In other embodiments, the epicatechin is enatiomerically pure or enantiomerically enriched (-) epicatechin. The purity of the enantiomerically pure or enantiomerically enriched (+)/(-) epicatechin is at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100%.
  • the epicatechin comprises at least about 75% (+)-epicatechin, such as at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or greater, (+)-epicatechin.
  • the epicatechin comprises at least about 75% (-)-epicatechin, such as at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, 99.9%, or greater, (-)-epicatechin.
  • the epicatechin is in the form of a co-crystal.
  • Co-crystals of epicatechin have been previously described, for example, in US2021/0380535, which is hereby incorporated by reference in its entirety.
  • Co-crystals described herein can have a purity of at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.8%, or 99.9%.
  • the co-crystal is a co-crystal of (+) epicatechin : trigonelline.
  • the co-crystal is a co-crystal of (-) epicatechin : trigonelline. In some embodiments, the co-crystal is a co-crystal of (+) epicatechin : D-proline. In some embodiments, the co-crystal is a co-crystal of (+) epicatechin : L-proline.
  • provided herein is a method of treating or preventing a condition related to acute or chronic excessive glutamate exposure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the phrase “excessive glutamate exposure” refers to an amount of glutamate that induces excessive stimulation of glutamate receptors. In some embodiments, the excessive glutamate exposure results from increased extracellular glutamate concentrations. In some embodiments, the excessive glutamate exposure results from excessive glutamate release from the presynaptic membrane. In some embodiments, the excessive glutamate exposure results from impaired glutamate reuptake function. In some embodiments, the excessive glutamate refers to glutamate levels that are increased by greater than any of about 0.05-fold, 0.1-fold, 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or more, compared to the glutamate levels prior to exci totoxi city.
  • the excessive glutamate refers to glutamate levels that are increased by less than any of about 5-fold, 4- fold, 3-fold, 2-fold, 1-fold, 0.5-fold, 0.1-fold, 0.05-fold, or less, compared to the glutamate levels prior to excitotoxicity.
  • the excessive glutamate exposure causes glutamate excitotoxicity.
  • Glutamate excitotoxicity is the excessive stimulation of glutamate receptors, such as N-methyl-D-aspartate (NMDA) receptors, a-amino-3-hydroxy-5-methyl-4- isoxazol epropionic acid (AMP A) receptors, and/or kainate receptors.
  • glutamate excitotoxicity may induce neuronal degeneration, such as degeneration of dopaminergic neurons, thereby resulting in motor dysfunction.
  • the excessive glutamate exposure causes excessive stimulation of glutamate receptors.
  • the excessive glutamate exposure increases intracellular sodium (Na 2+ ) buildup. In some embodiments, the excessive glutamate exposure induces intracellular calcium (Ca 2+ ) buildup. In some embodiments, the intracellular Ca 2+ and/or Na 2+ is increased by greater than any of about 0.05-fold, 0.1-fold, 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or more, compared to the intracellular Ca 2+ and/or Na 2+ prior to the glutamate exposure.
  • the intracellular Ca 2+ and/or Na 2+ is increased less than about 5-fold, 4-fold, 3-fold, 2-fold, 1-fold, 0.5-fold, 0.1-fold, 0.05-fold, or less, compared to the intracellular Ca 2+ and/or Na 2+ prior to the glutamate exposure.
  • the intracellular Ca 2+ and/or Na 2+ buildup may cause neuronal damage.
  • the intracellular Ca 2+ and/or Na 2+ buildup may cause cell death.
  • the conditions for treatment or prevention related to acute or chronic excessive glutamate exposure may be any condition for which epicatechin is indicated, including, without limitation, any of the disease or conditions described in US 11,154,546, US 9,187,448, US 11,273,144, US2018/0193306, US 9,975,869, US 10,898,465, US2019/0262347, and US2021/0380535, each of which is hereby incorporated by reference in its entirety.
  • the condition is related to acute excessive glutamate exposure.
  • the condition is related to chronic excessive glutamate exposure.
  • the condition is selected from the group consisting of status epilepticus, neuroinflammatory disorders, pediatric seizure disorders, neuronal exocitoxicity, over activation of the NMDA receptor, post-operative syndromes of cognition loss, and loss of synaptic density.
  • ROS reactive oxygen species
  • the ROS may be any ROS known in the art.
  • the ROS comprises alpha-oxygen (a- O).
  • the ROS comprises superoxide (O’ U).
  • the ROS comprises a hydroxyl radical (OH’).
  • the ROS comprises a hydrogen peroxide (H2O2).
  • the ROS comprises singlet oxygen ( 1 O2).
  • the ROS comprises a combination of superoxide, hydroxyl radical, hydrogen peroxide, singlet oxygen, and/or alpha-oxygen. In some embodiments, the ROS is a result of acute or chronic excessive glutamate exposure. In some embodiments, the ROS is a result of acute or chronic exposure to intracellular Ca 2+ .
  • the subject in need of a method of decreasing ROS has a disease or disorder.
  • the disease or disorder may be any disease or disorder for which epicatechin is indicated, including, without limitation, any of the disease or conditions described in US 11,154,546, US 9,187,448, US 11,273,144, US2018/0193306, US 9,975,869, US 10,898,465, US2019/0262347, and US2021/0380535, each of which is hereby incorporated by reference in its entirety.
  • the subject has a disease or disorder selected from the group consisting of spinal cord injury or abnormality, liver disease, kidney disease, impaired cognition, neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, cardiomyopathy, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease, exocrine pancreatic insufficiency, impaired wound healing, and growth of cancer cells.
  • a disease or disorder selected from the group consisting of spinal cord injury or abnormality, liver disease, kidney disease, impaired cognition, neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, cardiomyopathy, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease,
  • the subject has a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • a method of treating a condition related to acute or chronic exposure to intracellular Ca 2+ in a subject in need thereof comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the exposure to intracellular Ca 2+ exposure results from excessive glutamate exposure.
  • the exposure to intracellular Ca 2+ exposure results from excessive glutamate release from the presynaptic membrane.
  • the exposure to intracellular Ca 2+ exposure results from impaired glutamate reuptake function.
  • the condition is related to acute exposure to intracellular Ca 2+ .
  • the condition is related to chronic exposure to intracellular Ca 2+ .
  • the condition may be any condition related to acute or chronic exposure to intracellular Ca 2+ .
  • the acute or chronic exposure to intracellular Ca 2+ is caused by excessive glutamate exposure.
  • the excessive glutamate exposure is acute excessive glutamate exposure.
  • the excessive glutamate exposure is chronic excessive glutamate exposure.
  • the condition is neuronal excitotoxicity. In some embodiments, the condition is glutamate excitotoxicity.
  • a method of lowering intracellular Ca 2+ levels in a subject in need thereof comprising administering to the subject a therapeutically effective amount of epicatechin or a pharmaceutically acceptable salt thereof.
  • the Ca 2+ levels are reduced by greater than any of about 0.05-fold, 0.1-fold, 0.5-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, or more, compared to the intracellular Ca 2+ prior to performing a method described herein.
  • the Ca 2+ levels are reduced by less than any of about 5-fold, 4-fold, 3-fold, 2-fold, 1-fold, 0.5-fold, 0.1-fold, 0.05-fold, or less, compared to the intracellular Ca 2+ prior to performing a method described herein.
  • the subject in need of a method of lowering intracellular Ca 2+ levels has a disease or disorder.
  • the disease or disorder may be any disease or disorder for which epicatechin is indicated, including, without limitation, any of the disease or conditions described in US 11,154,546, US 9,187,448, US 11,273,144, US2018/0193306, US 9,975,869, US 10,898,465, US2019/0262347, and US2021/0380535, each of which is hereby incorporated by reference in its entirety.
  • the subject has a disease or disorder selected from the group consisting of spinal cord injury or abnormality, liver disease, kidney disease, impaired cognition, neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, cardiomyopathy, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease, exocrine pancreatic insufficiency, impaired wound healing, and growth of cancer cells.
  • a disease or disorder selected from the group consisting of spinal cord injury or abnormality, liver disease, kidney disease, impaired cognition, neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, cardiomyopathy, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease,
  • the subject has a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Leigh syndrome, Duchenne muscular dystrophy, Becker muscular dystrophy, and peripheral and central neuropathies.
  • the epicatechin or pharmaceutical composition thereof may be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state.
  • a therapeutically effective dosage e.g., a dosage sufficient to provide treatment for the disease state.
  • human dosage levels have yet to be optimized for the chemical entities described herein (e.g., epicatechin, co-crystals of epicatechin, etc.)
  • a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight.
  • the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day.
  • the epicatechin is administered each day, every other day, weekly, every two weeks, every three weeks, or every four weeks.
  • the amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day
  • an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the pharmacokinetics.
  • the epicatechin is administered at a daily dosage of between about 5 mg to about 500 mg, such as between about 5 mg and about 100 mg, about 50 mg and about 200 mg, about 100 mg and about 300 mg, about 200 mg and about 400 mg, or about 300 mg and about 500 mg. In some embodiments, the epicatechin is administered at a daily dosage of less than about 500 mg, such as less than any of about 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg, or less.
  • the epicatechin is administered at a daily dosage of greater than about 5 mg, such as greater than any of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or greater, [0070]
  • a daily dose is the total amount administered in a day.
  • a daily dose may be, but is not limited to be, administered each day, every other day, each week, every 2 weeks, every month, or at a varied interval.
  • the daily dose is administered for a period ranging from a single day to the life of the subject.
  • the daily dose is administered once a day.
  • the daily dose is administered in multiple divided doses, such as in 2, 3, or 4 divided doses.
  • the daily dose is administered in 2 divided doses.
  • Administration of the epicatechin can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
  • the epicatechin or pharmaceutical composition thereof is administered orally, sublingually, subcutaneously, parenterally, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarily, vaginally, rectally, or intraocularly. In some embodiments, the epicatechin or pharmaceutical composition thereof is administered orally or intravenously. In some embodiments, the epicatechin or pharmaceutical composition thereof is administered orally.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms.
  • the epicatechin is administered in the form of a tablet, a capsule, a powder, a liquid, a suspension, a suppository, or an aerosol.
  • the epicatechin or pharmaceutical composition thereof can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate.
  • the epicatechin or pharmaceutical composition thereof are provided in unit dosage forms suitable for single administration of a precise dose.
  • the epicatechin or pharmaceutical composition thereof can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate).
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate).
  • the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the epicatechin or pharmaceutical composition thereof will take the form of a pill or tablet and thus the composition may contain, along with epicatechin (e.g., an epicatechin co-crystal), one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives).
  • a diluent e.g., lactose, sucrose, dicalcium phosphate
  • a lubricant e.g., magnesium stearate
  • binder e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives.
  • Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate,
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a co-crystal disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of the epicatechin contained in such parenteral compositions depends, for example, on the physical nature of the co-crystal, the activity of the epicatechin, and the needs of the subject.
  • compositions of epicatechin may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
  • compositions can include epicatechin, epicatechin cocrystals, and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • the epicatechin is administered in the form of a pharmaceutical composition comprising the epicatechin or the pharmaceutically acceptable salt, solvate, or co-crystal thereof, and a pharmaceutically acceptable excipient.
  • the epicatechin may be administered in combination with one or more additional therapeutic agents. In some embodiments, the epicatechin and the one or more additional therapeutic agents are administered concurrently. In some embodiments, the epicatechin and the one or more additional therapeutic agents are administered sequentially.
  • the article of manufacture may comprise a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may hold a pharmaceutical composition provided herein.
  • the label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
  • kits containing epicatechin such as epicatechin, a co-crystal of epicatechin, or pharmaceutical compositions thereof, described herein and instructions for use.
  • the kits may contain instructions for use in the treatment of any disorder, disease, or condition, provided herein in a subject in need thereof.
  • a kit may additionally contain any materials or equipment that may be used in the administration of the epicatechin, such as epicatechin, a co-crystal of epicatechin, or pharmaceutical compositions thereof, such as vials, syringes, or IV bags.
  • a kit may also contain sterile packaging.
  • Example 1 Epicatechin blocks NMDA induced neuronal toxicity in primary cortical neurons
  • (+)-epicatechin (z.e., EPM-01) and (-)-epicatechin (z.e., EPM-03) block N-methyl-D-aspartate (NMDA) induced neuronal toxicity in vitro in primary cultures of rat cortical neurons.
  • NMDA N-methyl-D-aspartate
  • the cells were maintained in Neurobasal medium supplemented with B27, 2 mM glutamine, 25 mM glucose, and antibiotic solution consisting of penicillin (100 U/mL) and streptomycin (100 mg/mL), in a humidified atmosphere at 37 °C, with 5% CO2. Half-media changes were performed every 4-5 days, or as required. All experiments were conducted at 12-14 DIV.
  • EPM-01 z.e., (+)- epicatechin
  • EPM-03 z.e., (-)-epicatechin
  • EPM-06 z.e., 11 -hydroxypregnenolone
  • EPM- 07 z.e., 11- hydroxyprogesterone
  • catechin at various concentrations for 30 minutes.
  • Neurons were then exposed to 20 or 25 uM of NMDA, determined by a dose response curve, for 30 minutes. After NMDA exposure, media with test compounds was replaced and the cells were allowed to recover for 18-24 hours.
  • NMDA ntiter-Glo Luminescent Cell Viability Assay (Promega) was used. Luminescence was measured according to manufacturer (BMG LABTECH CLARIOstar) instructions.
  • FIGS. 1 A-1E the addition of NMDA caused a decrease in neuronal survival.
  • Primary cortical neurons treated with EPM-01 at 10 pM, 1 nM, and 10 nM showed increased survival, compared to vehicle treated neurons (FIG. 1 A).
  • Primary cortical neurons treated with EPM-03 at 0.1 pM, 10 pM, and 0.1 nM showed increased survival, compared to vehicle treated neurons (FIG. IB).
  • EPM-06, EPI-07, and catechin treatment did not increase survival in primary cortical neurons exposed to NMD A (FIGS. 1C-1E).
  • Example 2 Epicatechin improves fESPS recovery following NMDA activation or oxygen-glucose deprivation (OGD) ex vivo
  • This Example shows that epicatechin improves field excitatory postsynaptic potential (fESPS) in a translational model exci totoxi city using brain slices from rats.
  • Brain slices (FIGS. 2A-2B) were exposed to NMDA or oxygen-glucose deprivation (OGD), either in the presence or absence of EPM-01 (z.e., (+)-epicatechin), according to standard protocols.
  • OGD oxygen-glucose deprivation
  • the OGD model leads to lack of ATP production and opening of the glutamate receptors and channels, resulting in neuronal cell death.
  • Field excitatory postsynaptic potential (fESPS) was measured to determine how epicatechin influences ion transport required to reset the neuron back to its resting membrane potential.
  • the fEPSP amplitude was measured as the difference between the baseline (before stimulation) and the maximal peak amplitude.
  • the population spike was measured as peak to peak amplitude.
  • fEPSPs and population spikes needed to be stable (less than 15% fluctuation) and larger than 100 pV during the baseline.
  • Data from each electrode in a given slice were averaged and the slice was considered as an individual sample (n).
  • the distribution of raw amplitudes between groups was plotted as a scatter plot.
  • the normalized amplitude values ( ⁇ SEM) were plotted as a function of time. The percentage of change over the last 2 minutes of each period of vehicle or compound application (in regards to the baseline period) were plotted in a scatter plot with each slice considered as an individual sample (n).
  • Example 3 Epicatechin protects against neuroinflammatory disorders in vivo in a mouse model
  • This Example shows the effects of epicatechin (EPM-01) treatment on mice with neuroinflammatory disorders.
  • EPM-01 epicatechin
  • R6/2 mice dosed with EPM-01 had lower mortality than vehicle-dosed R6/2 mice.
  • EPM-01 had limited effects on behavior of R6/2 mice, but seemed to reduce seizures in R6/2 mice and to reduce freezing in non-carrier controls.
  • EPM-01 displayed anti-inflammatory properties in R6/2 mice brains compared to the vehicle treated controls suggesting its utility and anti-inflammatory mode of action for the treatment of central nervous system (CNS) disorders.
  • CNS central nervous system
  • mice from Jackson Laboratory (Stock# 006494; B6CBA-Tg(HDexonl)62Gpb/3J) and wild-type (WT) littermates were used in the study.
  • the experimental groups are described in Table 1.
  • Mice received daily treatment of EPM-01 (z.e., (+)-epicatechin) (3 mg/kg, Per Oral) or vehicle (0.5% Carboxymethylcellulose sodium salt in water) starting at 5 weeks old until 16 weeks old for tissue collection.
  • EPM-01 z.e., (+)-epicatechin
  • vehicle 0.5% Carboxymethylcellulose sodium salt in water
  • Behavioral tests included Activity Chamber (AC), Rotarod (RR), Novel Cage Observation (NCO) and Fear Conditioning (FC).
  • AC Activity Chamber
  • RR Rotarod
  • NCO Novel Cage Observation
  • FC Fear Conditioning
  • weekly Body Weight, Clinical Score, Body Condition Score, Neurological Score and Survival follow up were performed throughout the study. Tissue samples were collected at the end of study for ex vivo analysis. Brain, plasma, heart, liver, lungs, spleen, gastrocnemius muscle, kidneys, and testes were collected. Table 1, below outlines the experimental design.
  • the Activity Chamber is used to determine general activity levels, gross locomotor activity, and exploration habits in rodents. The assessment took place in an Open Field Activity Arena (Med Associates Inc., St. Albans, VT. Model ENV-515) mounted with three planes of infrared detectors, within a specially designed sound-attenuating chamber (Med Associates Inc., St. Albans, VT. MED-017M-027).
  • the arena is 43cm (L) x 43cm (W) x 30cm (H) and the sound-attenuating chamber is 74cm (L) x 60cm (W) x 60cm (H).
  • mice were placed in the comer of the testing arena and allowed to explore the arena for 10 minutes while being tracked by an automated tracking system. Parameters including Distance moved, velocity, rearing, and times spent in periphery and center of the arena were analyzed. The periphery was defined as the zone 5cm away from the arena wall. The arena was cleaned with a 1% Virkon solution at the end of each trial. AC was conducted at 5, 8 and 11 weeks postdosing.
  • R6/2 mice have deficits in Distance Moved, Vertical Count, Vertical Time, and Duration in the Center of the Arena as detected in the Activity Chamber (FIGS. 5A-5D).
  • the Rotarod test is designed to evaluate the motor coordination and balance of mice by allowing the mice to locomote on a rotating rod (Med Associate Inc, Model ENV-575M) elevated 16.5cm above the testing floor.
  • the experiment consisted of one day of training and one day of testing. On the training day, mice were placed on the rod at a fixed speed of 4rpm for 1 minute. They were returned to the home cage after training. On the testing days, the mice were tested with an accelerating speed of 4-40rpm for maximum duration of 5 minutes. They were tested for 3 trials per day with 15-20 minutes inter-trial-intervals (ITIs). A 4th trial was tested on the mice that hold onto the rod for 2 consecutive revolutions or falls within 5 seconds of the start of a trial.
  • ITIs inter-trial-intervals
  • the Novel Cage Observation is an assessment used to determine general activity levels, locomotion activity and exploration habits in a novel cage environment. NCO was conducted at 6, 9, 12, and 13 weeks post-dose. Each mouse was placed in the center of a clean cage and allowed to freely move while tracked by an automated tracking system Ethovision XT software. The distance moved and average velocity were acquired over the 5 minutes trial. An experimenter blind to the treatment groups assessed other parameters such as digging, grooming, rearing, climbing, and seizure duration.
  • FIG. 7H A behavioral phenotype for R6/2 mice in novel cage observation was observed across multiple individual measures (FIGS. 7A-7G). Comparison of R6/2 mice dosed with EPM-01 relative to R6/2 mice dosed with vehicle was not significant for any of the measures.
  • FIG. 7H Regarding seizure duration (FIG. 7H), at 13 weeks average seizure duration was elevated in R6/2 vehicle-dosed mice but not R6/2 EPM-01 -dosed mice relative to non-carrier vehicle dosed mice. This effect is likely due to a greater percentage of mice in the R6/2 vehicle-dosed group (5 out of 12; 41.7%) having seizures than in the R6/2 EPM-01 dosed group (2 out of 13; 15.4%). No mice had seizures in the non-carrier groups.
  • the Fear Conditioning (FC) assay is an associative learning task in which mice learn to associate a particular neutral Conditional Stimulus (CS; a context) with an aversive Unconditional Stimulus (US; a mild electrical foot shock) and show a Conditional Response (CR; freezing).
  • the experiment consisted of 1 day of Training and 1 day of Contextual testing.
  • the chamber walls were made of aluminum; the floor was a gray metal grid through which the US (shock) was delivered.
  • the conditioning was conducted under yellow light and the chamber was scented with mint extract to produce a unique smell.
  • the chambers were cleaned with a 10% simple green solution (Sunshine Makers, Inc.) between each mouse. Chambers were mounted on the wall and includes an exhaust fan and camera.
  • mice were placed individually into a training chamber for 90 seconds. Three electrical shocks (intensity 0.5mA, 2 seconds) were presented 90s apart and mouse was removed from the chamber 90s after the last shock. On Day 2, the mice were placed back into the training chamber without any shock for contextual memory testing for 5 minutes.
  • Tissue cytokines were analyzed in brain homogenate from hippocampal-containing dissections from frozen coronal sections spanning the rostrocaudal extent of the hippocampus, using a Luminex 48-plex mouse cytokine assay.
  • the Luminex assay was performed in the Human Immune Monitoring Center at Stanford University, following manufacturer instructions. Briefly, hippocampal tissue was homogenized in lysis buffer containing proteinase inhibitor by pulling tissue through a 23 g needle (15x) and then sonicated for 3x3 second pulses. Homogenate was spun at 14,000 g for 10 minutes, and protein concentrations were determined by Pierce BCA assay. Samples were diluted to a common concentration of 6 ug/uL. Brain homogenate samples were run in singlets on a 96 well plate alongside standard curve and quality control calibration samples.
  • EPM-01 had limited effects on behavior, including a tendency to reduce seizures in R6/2 mice and to reduce freezing in non-carrier controls.
  • Several markers of neuroinflammation in R6/2 mice were attenuated with EPM-01 treatment.
  • Example 4 Epicatechin mitigates disease phenotypes in CNS and neurodegenerative diseases of acute glutamate toxicity
  • Neurodegenerative diseases in which chronic glutamate toxicity has been implicated in disease progression examples of which include Parkinson’s disease, ALS, and Alzheimer’s disease, may also be evaluated in the clinic.

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Abstract

La présente invention concerne des méthodes de traitement ou de prévention d'une affection liée à une exposition critique ou chronique excessive à un glutamate à l'aide d'épicatéchine ou de compositions pharmaceutiques correspondantes L'invention concerne également des méthodes de diminution des dérivés réactifs de l'oxygène (ROS) et d'abaissement des niveaux intracellulaires de Ca2+ à l'aide d'épicatéchine ou de compositions pharmaceutiques correspondantes.
PCT/US2023/071953 2022-08-10 2023-08-09 Épicatéchine pour l'inhibition de la toxicité du glutamate WO2024036225A1 (fr)

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