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-10265338-B2
Publication Date
2019-04-23
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 provides compounds and methods for treating, ameliorating, or promoting recovery from conditions of the brain, central nervous system (CNS), or cardiovascular system, such as brain injuries, neurodegenerative conditions, or cardiac ischemia, by administering an effective amount of an agonist, partial agonist, or biased agonist of the A3 adenosine receptor (A3R) or the P2Y1 receptor. The invention includes compounds such as MRS4322, MRS1873, and others specified, which can selectively or preferentially activate specific signaling pathways associated with these receptors, thereby conferring neuroprotective, neurorestorative, cardioprotective, or cardioregenerative benefits.
The problem addressed by the invention is the lack of effective treatments for brain injury, CNS injury, heart and cardiovascular diseases, and neurodegenerative conditions like Alzheimer's, Parkinson's, and multiple sclerosis. Brain injuries and strokes are leading causes of death, disability, and economic burden, with the current absence of approved therapies for many of these conditions. There is a critical unmet need for treatments that can limit damage, enhance neuronal and glial survival, and promote functional recovery, particularly during acute injury and in chronic neurodegeneration.
The invention is based on the discovery that modulation of purinergic receptors—especially A3 adenosine and P2Y1 receptors—on astrocytes, neurons, and other brain or vascular cells can enhance neuroprotection, neurorestoration, and cardioprotection. This is achieved through selective or biased activation of receptor-mediated pathways, such as intracellular calcium mobilization, leading to improved cell viability during oxidative or metabolic stress. The compounds described possess properties (hydrophilicity, high unbound fraction) that allow better distribution and receptor interaction compared to traditional agonists.
Claims Coverage
The independent claims cover five main inventive features related to methods for treating CNS/brain injuries, neurodegenerative conditions, cardiovascular diseases, and increasing neuroprotection or cardioprotection using specific disclosed compounds.
Method of treating a brain or CNS injury or condition using specific compounds
This feature claims a method comprising administering to a patient an effective amount of a compound selected from those disclosed (which include various methanocarba nucleosides and pharmaceutically acceptable salts) to treat brain or CNS injury or condition, including but not limited to ischemic or hemorrhagic stroke.
Method of treating a neurodegenerative condition or condition mediated by brain injury
This inventive feature claims a method of administering an effective amount of a disclosed compound to a patient to treat neurodegenerative conditions, including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, or those resulting from traumatic brain injury and related brain pathology.
Method of treating a heart or cardiovascular disease with specified compounds
This inventive feature covers a method comprising administering an effective amount of a compound selected from the disclosed list to a patient for treating heart or cardiovascular diseases, including cardiac ischemia, myocardial infarction, and other cardiovascular disorders.
Method of treating a disease or condition by administering specified compounds
This inventive feature includes methods for treating a variety of diseases or conditions—such as otic disorders and pain—by administering an effective amount of the disclosed compounds to a patient in need thereof.
Method of increasing cardioprotection or regeneration of damaged heart tissue after ischemia or infarction
This covers a method of increasing cardioprotection or regeneration of damaged heart tissue in patients suffering from cardiac ischemia or myocardial infarction, by administering an effective amount of a disclosed compound.
The claims broadly protect the use of a defined set of compounds—primarily methanocarba nucleosides and their pharmaceutically acceptable salts—in methods for treating CNS, neurodegenerative, and cardiovascular conditions, including increasing neuroprotection and cardioprotection.
Stated Advantages
Enables neuroprotection and neurorestoration by promoting astrocyte-mediated survival signaling and enhancing resistance of neurons and other brain cells to injury and stress.
Facilitates cardioprotection and regeneration of damaged heart tissue following cardiac ischemia or myocardial infarction via A3R agonism.
Selectively activates desired receptor-mediated pathways (biased agonism), potentially reducing side effects associated with full or non-selective agonists.
Compounds with favorable physicochemical properties (high hydrophilicity, low protein binding) ensure higher unbound concentrations in plasma and brain, enhancing efficacy compared to lipophilic conventional agonists.
Effective in both acute injury settings (e.g., TBI, stroke) and chronic neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, MS, ALS, CTE).
Documented Applications
Treatment and recovery promotion after traumatic brain injury (TBI), including concussion, blast injury, and combat-related injury.
Acute and chronic treatment of stroke, including ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks (TIA).
Treatment of neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy.
Treatment of heart and cardiovascular diseases, including cardiac ischemia, myocardial infarction, cardiomyopathy, coronary artery disease, arrhythmia, and other listed disorders.
Treatment of conditions resulting from or mediated by brain injury or neurodegeneration, including deficits in cognition, CNS function, learning, memory loss, deafness, or ocular abnormalities.
Neuroprotection or regeneration in patients following brain surgery, cancer therapy, or exposure to toxins, as well as treatment of neurological side effects resulting from cancer chemotherapy.
Pain control, including pain mediated by the central nervous system, neuropathic pain, inflammatory pain, and acute pain.
Treatment of otic disorders, cancer of the brain (e.g., glioblastoma), gastrointestinal disorders, autoimmune diseases, allergic diseases, and prevention of transplant rejection.
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