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-9789131-B1
Publication Date
2017-10-17
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 relates to compounds and methods for treating, ameliorating, or promoting recovery from brain, central nervous system (CNS), or cardiovascular conditions, such as brain injuries, neurodegenerative conditions, or heart diseases. Specifically, the invention provides the use of agonists, partial agonists, or biased agonists of the A3 adenosine receptor (A3R), including compounds such as MRS4322 and its analogs, to achieve neuroprotective and neurorestorative effects, with an emphasis on enhancing astrocyte caretaker functions to improve cellular resistance to injury and neurodegeneration.
The problem addressed is the lack of effective treatments for brain and CNS injuries, including traumatic brain injury (TBI), stroke, and neurodegenerative diseases like Alzheimer's disease. The background highlights the high morbidity and mortality associated with these conditions, the inability of neurons to regenerate after injury, and the need for effective interventions to protect stressed brain cells, especially during the acute injury phase and for longer-term restoration in chronic or degenerative conditions.
The core innovation proposes the pharmacological use of selective or biased A3R modulators—either as single compounds or pharmaceutical compositions—to promote survival and recovery in patients suffering from brain or CNS injuries (such as TBI or stroke), neurodegenerative diseases, or heart and cardiovascular diseases. The invention details methods in which an effective amount of a disclosed compound, such as MRS4322 or MRS1873, is administered to modulate astrocyte and glial cell functions, resulting in improved neuroprotection, neurorestoration, and cardioprotection. This approach leverages the ability of the compounds to cross the blood-brain barrier and to achieve substantial free (unbound) concentrations in plasma and brain tissue for therapeutic action.
Claims Coverage
The patent includes two independent method claims, each defining specific inventive features relating to the treatment of neurological conditions using defined compounds.
Method of treating TBI or stroke with specified compounds
This inventive feature covers a method of treating a brain or central nervous system (CNS) injury or condition selected from traumatic brain injury (TBI) or stroke by administering to a patient in need thereof an effective amount of a compound selected from: - MRS4322 - MRS1873 The compounds may be administered as a pharmaceutically acceptable salt or in a pharmaceutically acceptable composition. The method also encompasses administration within defined time periods relative to the injury (such as within 24 hours or 8 hours of the TBI or stroke), and covers various forms of TBI (including, but not limited to, concussion, blast injury, combat-related injury, or mild, moderate, or severe blows to the head), with administration possible orally, intravenously, or parenterally. It additionally specifies that the neuroprotection or neurorestoration achieved is increased compared to an untreated patient.
Method of increasing neuroprotection or neurorestoration after TBI or stroke
This inventive feature covers a method of increasing neuroprotection or neurorestoration in a patient who has suffered a TBI or stroke, comprising administering to a patient in need thereof an effective amount of a compound selected from: - MRS4322 - MRS1873 The compounds can be in the form of their pharmaceutically acceptable salts or included in a pharmaceutically acceptable composition. The method specifies administration routes (oral, intravenous, or parenteral) and that the neuroprotection or neurorestoration decreases the recovery period after the TBI or stroke as compared with an untreated patient. The claims also set forth certain pharmacokinetic parameters, including compounds or salts with an unbound fraction in plasma of at least about 0.7 or at least about 0.08 unbound fraction in brain, or both.
The claims define methods of treating TBI or stroke and methods of increasing neuroprotection or neurorestoration by administering specific compounds, particularly MRS4322 and MRS1873 or their pharmaceutically acceptable salts, with features addressing both the time and modalities of administration, as well as pharmacokinetic properties ensuring effective exposure in plasma and brain.
Stated Advantages
The compounds, such as MRS4322 and MRS1873, provide increased neuroprotection and neurorestoration compared to untreated patients following TBI or stroke.
The compounds achieve substantial unbound concentrations in plasma and brain, making more active drug available at the therapeutic site compared to highly protein-bound alternatives.
The disclosed compounds are hydrophilic and can cross the blood-brain barrier efficiently, allowing for effective treatment of CNS injuries.
The methods can decrease the recovery period after TBI or stroke as compared with an untreated patient.
The invention offers a new approach for treating brain, CNS, and cardiovascular injuries and diseases through selective modulation of receptor-mediated pathways beneficial for neuroprotection and cardioprotection.
Documented Applications
Treatment and promotion of recovery from traumatic brain injury (TBI), including concussion, blast injury, combat-related injury, and mild to severe blows to the head.
Treatment and recovery from stroke, including ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks (TIA).
Increasing neuroprotection and neurorestoration in patients who have suffered TBI or stroke.
Treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and chronic traumatic encephalopathy (CTE).
Treatment or amelioration of heart or cardiovascular diseases, including cardiac ischemia, myocardial infarction, cardiomyopathy, coronary artery disease, arrhythmia, myocarditis, pericarditis, angina, hypertensive heart disease, endocarditis, rheumatic heart disease, congenital heart disease, or atherosclerosis.
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