Compounds and methods for treating neurological and cardiovascular conditions
Inventors
Korinek, William S. • Lechleiter, James D. • Liston, Theodore E. • Jacobson, Kenneth A.
Assignees
University of Texas System • Astrocyte Pharmaceuticals Inc • US Department of Health and Human Services
Publication Number
US-12239654-B2
Publication Date
2025-03-04
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 invention provides compounds and methods for treating, ameliorating, or promoting recovery from disorders and conditions of the brain, central nervous system (CNS), or cardiovascular system, such as brain injury, neurodegenerative conditions, or cardiac ischemia. The methods comprise administering an effective amount of an agonist, partial agonist, or biased agonist of the A3 adenosine receptor (A3R) or P2Y1 receptor to a patient in need.
The invention addresses the urgent need for effective treatments for brain injuries, CNS injuries, heart and cardiovascular diseases, and related conditions, as well as promoting neurorestoration in neurodegenerative disorders like Alzheimer’s disease. Brain injuries cause neurons to die, which cannot be replaced, resulting in irreversible cognitive and sensorimotor deficits. There is a critical period, especially within the first 24 hours following injury, where intervention can limit damage propagation and improve recovery outcomes, an area that current treatments insufficiently address.
The core innovation lies in modulating purinergic receptors, specifically A3R and P2Y1, on astrocytes and other neural cells, thereby enhancing neuroprotective and neurorestorative pathways. The activation of these receptors using specific agonists or biased agonists increases astrocyte caretaker functions, energy metabolism, and antioxidant production, which maintains neuronal viability after stress, such as ischemia or traumatic injury. Some compounds, like MRS4322, are designed to be hydrophilic with high unbound fractions, optimizing their brain and plasma availability compared to traditional A3 agonists.
Claims Coverage
The primary independent claim covers a method for treating traumatic brain injury and various forms of stroke using specific compounds.
Method of treating brain injury or stroke with specified compounds
The inventive feature is the administration of an effective amount of a compound selected from specified methanocarba nucleosides or their pharmaceutically acceptable salts or compositions to a patient in need, where the injury, disease, or condition is traumatic brain injury (TBI) or stroke (selected from ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks).
The claim establishes the use of certain methanocarba nucleosides or their salts in methods for treating traumatic brain injury and stroke, defining the eligible conditions and specifying the compounds for the therapeutic intervention.
Stated Advantages
Compounds exhibit neuroprotective and neurorestorative effects by enhancing astrocyte caretaker functions and promoting neuronal survival after injury.
The hydrophilic nature and low plasma and brain binding of some compounds (such as MRS4322 and MRS1873) result in high unbound drug concentrations available to interact with target receptors.
Biased agonism at A3 adenosine receptors enables preferential activation of neuroprotective and/or cardioprotective pathways, potentially reducing side effects compared to full agonists.
Treatment can decrease recovery time after TBI or stroke and increase neuroprotection or neurorestoration as compared to untreated patients.
Compounds cross the blood-brain barrier and are detectable in plasma, brain, and cerebrospinal fluid, supporting their use in neurological indications.
Documented Applications
Treatment of traumatic brain injury (TBI), including concussion, blast injury, combat-related injury, or mild, moderate, or severe head trauma.
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 or cardiovascular diseases including cardiac ischemia and myocardial infarction.
Treatment of migraine headache, radiation damage, neurological side effects associated with cancer chemotherapy or brain surgery, and cases involving neurorestoration.
Treatment of patients who are at risk of brain injury or stroke or those experiencing long-term symptoms associated with neurodegenerative conditions.
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