Compounds and methods for treating neurological and cardiovascular conditions
Inventors
Korinek, William S. • Lechleiter, James D. • Liston, Theodore E.
Assignees
University of Texas System • Astrocyte Pharmaceuticals Inc
Publication Number
US-10953031-B2
Publication Date
2021-03-23
Expiration Date
2037-04-21
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Abstract
The present invention relates to compounds and methods of use thereof for treatment of certain disorders and conditions, for example brain injuries such as stroke or traumatic brain injuries.
Core Innovation
The present invention relates to the discovery and use of specific compounds and methods for treating, ameliorating, or promoting recovery from neurological and cardiovascular conditions, including brain injuries such as traumatic brain injury (TBI), stroke, neurodegenerative disorders, and heart or cardiovascular diseases. The method primarily involves administering to a patient in need thereof an effective amount of an agonist, partial agonist, or biased agonist of an A3 adenosine receptor (A3R), or a compound acting on purinergic P2Y1 receptors. The compounds disclosed include 2-methylthioadenosine and its pharmaceutically acceptable salts, among other specified analogs.
The invention addresses the urgent and unmet need for effective treatments for brain injuries, central nervous system injuries, cardiovascular diseases, and neurodegenerative conditions. Existing challenges include the irreversible loss of neurons due to limited regenerative capacity, inadequate neurorestorative mechanisms, and the lack of approved therapies—especially for acute injury phases and for long-term neurodegenerative disease management. The disclosed compounds offer potential for both acute neuroprotection and longer-term neurorestoration or cardioprotection by modulating the relevant receptor pathways.
In particular, the invention exploits the selective and biased activation or partial agonism of A3 adenosine receptors or P2Y1 receptors to enhance neuroprotective, neurorestorative, or cardioprotective signaling while minimizing activation of undesired pathways. This selective modulation may improve therapeutic outcomes by increasing astrocyte caretaker functions, promoting cell survival signaling, reducing reactive gliosis and excitotoxicity, and increasing resistance of brain and heart cells to injury and stress. The compounds are effective across a range of routes (oral, intravenous, parenteral) and demonstrate favorable pharmacokinetics including adequate blood-brain barrier penetration, high unbound drug concentrations, and efficacious action in multiple animal models.
Claims Coverage
The patent contains five independent claims, each addressing a distinct therapeutic method employing 2-methylthioadenosine or its derivatives for treating specific disease or condition categories.
Treatment of pain conditions with 2-methylthioadenosine
The inventive feature is the method of treating diseases or conditions selected from pain control, pain mediated by the CNS, neuropathic pain, inflammatory pain, or acute pain by administering to a patient in need thereof an effective amount of 2-methylthioadenosine.
Treatment of TBI or stroke with 2-methylthioadenosine
The inventive feature is the method of treating a disease or condition selected from traumatic brain injury (TBI) or stroke by administering to a patient in need thereof an effective amount of 2-methylthioadenosine.
Treatment of stroke and related cerebrovascular conditions with 2-methylthioadenosine
The inventive feature is the method of treating a disease or condition selected from ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, or transient ischemic attacks (TIA) by administering to a patient in need thereof an effective amount of 2-methylthioadenosine.
Increasing neuroprotection or neurorestoration after TBI or stroke with 2-methylthioadenosine
The inventive feature is the method of increasing neuroprotection or neurorestoration in a patient who has suffered a traumatic brain injury (TBI) or stroke by administering to a patient in need thereof an effective amount of 2-methylthioadenosine.
Increasing cardioprotection or regeneration after heart tissue damage with 2-methylthioadenosine
The inventive feature is the method of increasing cardioprotection or regeneration of damaged heart tissue in a patient who has suffered a cardiac ischemia or myocardial infarction by administering to a patient in need thereof an effective amount of 2-methylthioadenosine.
The independent claims broadly cover methods of using 2-methylthioadenosine for treating pain, TBI, stroke, various cerebrovascular events, enhancing neuroprotection/restoration, and increasing cardioprotection or heart tissue regeneration.
Stated Advantages
The compounds provide effective neuroprotective and neurorestorative effects in brain injuries, stroke, and neurodegenerative disorders by selectively modulating relevant receptor pathways.
Rapid distribution and high unbound fraction in plasma and brain result in greater drug availability to interact with target receptors, enhancing efficacy compared to conventional A3 adenosine receptor agonists.
Selective or biased receptor agonism may improve treatment specificity by activating protective pathways while minimizing unwanted side effects.
Compounds cross the blood-brain barrier and are effective via routes suitable for clinical use (oral, intravenous, parenteral).
Demonstrated reduction in biomarkers of neuroinflammation and brain infarct size in animal models supports their neuroprotective efficacy.
Documented Applications
Treatment of pain conditions, including pain control, pain mediated by the CNS, neuropathic pain, inflammatory pain, and acute pain.
Treatment of traumatic brain injury (TBI), including concussion, blast injury, combat-related injury, or mild, moderate, or severe blows to the head.
Treatment of stroke, including ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks (TIA).
Increasing neuroprotection or neurorestoration for patients recovering from TBI or stroke.
Increasing cardioprotection or regeneration of damaged heart tissue in patients who have suffered cardiac ischemia or myocardial infarction.
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