Methanocarba derivatives of pseudoribose that inhibit adenosine kinase
Inventors
Jacobson, Kenneth Alan • Boison, Detlev • Toti, Kiran Shambhu
Assignees
Legacy Emanuel Hospital and Health Center • US Department of Health and Human Services
Publication Number
US-10016432-B2
Publication Date
2018-07-10
Expiration Date
2037-05-26
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Abstract
Adenosine kinase inhibitors, including pharmaceutical compositions containing the adenosine kinase inhibitors, and their use for preventing epilepsy and its progression in patients. The adenosine kinase inhibitors have the formula: where the moieties J and K, considered in combination, are —CH2—, or K and L, considered in combination, are —CH2—. The R1 moiety can be —NH2, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl. The R2 and R3 moieties are each independently C1-C6 alkyl. The R4 moiety is hydrogen or C1-C6 alkyl. The R5 and R6 moieties are each independently C6-C12 aryl, C3-C8 cycloalkyl, or C3-C8 heteroaryl, that is optionally further substituted.
Core Innovation
The invention relates to a novel family of adenosine kinase (AdK) inhibitors, specifically methanocarba derivatives of pseudoribose, aimed at preventing epilepsy and its progression in patients. These inhibitors possess a distinct bicyclic methanocarba ring system that sterically constrains the ribose-like ring into either a North (N) or South (S) conformation, enhancing selectivity and potency toward human AdK. The disclosed inhibitors have a defined chemical formula with specific substituents R1 to R6 and ring moieties J, K, and L that form either a cyclopropane ring fused to a cyclopentane or other conformations, enabling them to inhibit AdK effectively.
The problem addressed is that endogenous adenosine levels in the brain, regulated mainly by AdK, influence seizure suppression and epilepsy progression via receptor-dependent and independent mechanisms, including epigenetic DNA methylation pathways. Existing AdK inhibitors, including riboside derivatives like 5-iodotubercidin, have off-target effects, low blood-brain barrier penetration, and adverse side effects such as brain hemorrhage. Therefore, there is a need for brain-penetrant, isoform- and cell-type-selective AdK inhibitors that effectively raise brain adenosine levels without excessive receptor activation or toxic side effects. The invention also aims to provide inhibitors with enhanced selectivity toward the nuclear isoform of AdK (ADK-L) to target epigenetic modifications associated with epilepsy progression.
Claims Coverage
The claims define a set of adenosine kinase inhibitors with specific chemical formulas and their pharmaceutical compositions, along with methods for treating epilepsy using these compounds. There are multiple independent claims focusing on the chemical structure, composition, and method of administration.
Adenosine kinase inhibitors with methanocarba ring systems
The invention claims adenosine kinase inhibitors comprising a bicyclic methanocarba pseudoribose moiety wherein either J and K or K and L together form a —CH2— (cyclopropane) bridge fused to a cyclopentane ring. The inhibitors have specific substituents R1 through R6, including amino, alkyl, alkoxy, hydroxyalkyl, aryl, cycloalkyl, and heteroaryl groups, where R5 and R6 can be optionally further substituted. These structural features define the core scaffold of the adenosine kinase inhibitors.
Pharmaceutical compositions containing the described methanocarba adenosine kinase inhibitors
Claims cover pharmaceutical compositions comprising the specified adenosine kinase inhibitors with the defined chemical formula, formulated with pharmaceutically acceptable carriers, excipients, preservatives, and/or diluents to facilitate administration by intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal, or topical routes.
Methods for treating epilepsy by administering the methanocarba inhibitors
Claims include methods of preventing or treating epilepsy and its progression in patients by administering an effective amount of the described adenosine kinase inhibitors. Administration routes include various medically acceptable modes such as intravenous, oral, transdermal, subcutaneous, mucosal, intramuscular, intranasal, intrapulmonary, parenteral, intrarectal, and topical routes. The method involves inhibiting epileptic seizures via selective AdK inhibition.
The independent claims collectively cover the chemical structure of novel methanocarba-based adenosine kinase inhibitors, their pharmaceutical formulations, and therapeutic methods of epilepsy treatment using these inhibitors administered via multiple suitable routes.
Stated Advantages
The inhibitors are designed to selectively target AdK, particularly the nuclear isoform ADK-L, to modulate epigenetic DNA methylation linked to epilepsy progression, providing a dual pharmacological and epigenetic mechanism of action.
The bicyclic methanocarba ring constraint enhances inhibitor potency and selectivity by fixing the ribose-like ring in preferred conformations, potentially reducing off-target effects seen with prior riboside inhibitors.
Slightly increased hydrophobicity compared to ribosides may improve blood-brain barrier permeability, facilitating central nervous system activity.
The novel inhibitors exhibit specificity without non-specific epigenetic off-target effects, demonstrated by in vitro and in vivo tests with reduced sedative side effects compared to known inhibitors like 5-iodotubercidin.
Targeting ADK-L avoids excessive extracellular adenosine generation associated with adverse effects, thereby enhancing safety.
Transient dosing regimens may provide long-lasting benefits through epigenetic reprogramming while minimizing toxicities from chronic administration.
Documented Applications
Pharmaceutical compositions and methods for preventing epilepsy and its progression by administering the methanocarba-derived adenosine kinase inhibitors.
Use of the inhibitors to inhibit seizures and treat epilepsy through modulation of brain adenosine levels and epigenetic DNA methylation mechanisms.
Potential treatment of disorders characterized by pathological overexpression of adenosine kinase, including Parkinson's disease, Alzheimer's disease, and cancer.
Administration techniques include systemic routes such as oral, intravenous, and topical, as well as direct brain administration via intracranial injection or during surgical procedures to prevent secondary epileptogenesis.
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