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-11484545-B2
Publication Date
2022-11-01
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 of use for treating, ameliorating, or promoting recovery from conditions affecting the brain, central nervous system (CNS), and cardiovascular system, such as brain injuries (including traumatic brain injury and stroke), neurodegenerative conditions, and heart or cardiovascular diseases. The core approach involves administering to a patient an effective amount of a compound that acts as an agonist, partial agonist, or biased agonist at the A3 adenosine receptor (A3R), or in some cases, the P2Y1 receptor, to achieve neuroprotective, neurorestorative, and/or cardioprotective effects.
The problem addressed is that brain injuries and neurodegenerative conditions cause loss or damage to neurons, which have limited capacity for repair. Following injury or ischemia (such as stroke), stressed but viable brain tissue (penumbra) is vulnerable to further damage due to disturbances in ion homeostasis, excitotoxicity, and cell death. There is a crucial period within 24 hours post-injury where intervention can protect the at-risk cells, and yet effective treatments to do so are lacking. Similarly, heart tissues subjected to ischemia can benefit from new approaches to cardioprotection.
This invention demonstrates that selective activation or biased modulation of A3R (and in some embodiments P2Y1 receptors) can enhance astrocyte caretaker functions, boost energy metabolism, and promote neuronal and cardiac cell survival during acute injury and chronic degeneration. The patent includes specific compounds, such as MRS4322 and MRS1873, designed with properties to maximize unbound drug concentration in plasma and brain and exhibit functional selectivity (biased agonism) at A3R, thereby offering improved neuroprotection and cardioprotection over traditional full agonists.
Claims Coverage
There are two independent claims in the patent, each introducing distinct inventive features focusing on methods of treating cognition- and pain-related disorders with specific compounds.
Treating cognitive, CNS, learning, or memory deficits with specified compounds
This inventive feature consists of a method of treating a disease, disorder, or condition selected from deficit in cognition, deficit in CNS function, deficit in learning, and memory loss by administering to a subject in need thereof an effective amount of a compound selected from a specified group including MRS4322 and related nucleoside analogs. - The method is applicable to subjects with conditions resulting from traumatic brain injuries or strokes, including ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, transient ischemic attacks (TIA), or Alzheimer's disease. - The improvement is measured as a score increase between about 1% and 20% in the delayed verbal recall task of the revised Wechsler Memory Scale. - The method covers increasing synaptic plasticity, improving hippocampal long-term potentiation, improving cognitive function, decreasing cognitive impairment, and improving or restoring memory or learning.
Treating pain by administering specified nucleoside analogs
This inventive feature involves a method of treating pain by administering to a subject in need thereof an effective amount of a compound selected from a group including MRS4322 and related analogs. - The method covers various types of pain, including neuropathic, inflammatory, acute, chronic, nociceptive, and non-inflammatory musculoskeletal pain (such as fibromyalgia syndrome, myofascial pain syndrome), as well as pain associated with a broad range of clinical conditions (including otic, musculoskeletal, gastrointestinal, cancer-related, nerve injury, migraine, and more). - The claim encompasses administration for both direct treatment and for pain associated with other disorders or procedures.
In summary, the claims broadly cover methods of treating cognitive, CNS, learning, and memory deficits, as well as various types of pain, through administration of specified compounds, especially those exhibiting activity at A3 adenosine receptors.
Stated Advantages
The invention provides compounds with high unbound fractions in plasma and brain, resulting in more effective concentrations available for neuroprotective or cardioprotective activity.
Selective or biased agonism at A3 adenosine receptors enhances neuroprotective pathways while minimizing undesired pathway activation, potentially reducing side effects.
The compounds are effective in protecting against further brain damage in acute injury situations (such as stroke or traumatic brain injury) and in promoting recovery.
The invention offers therapeutic benefit in neurodegenerative diseases by promoting neurorestoration and improving cognitive or neurological function.
The compounds can be used for cardioprotection in conditions like cardiac ischemia, potentially aiding in tissue regeneration and limiting damage.
Documented Applications
Treatment or amelioration 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, or transient ischemic attacks (TIA).
Treatment and neuroprotection or neurorestoration in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and chronic traumatic encephalopathy (CTE).
Treatment of 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.
Treatment or management of deficits in cognition, CNS function, learning, memory loss, and cognitive impairment, including those associated with TBI, stroke, or Alzheimer's disease.
Treatment of various types of pain, including neuropathic, inflammatory, acute, chronic, nociceptive, non-inflammatory musculoskeletal pain (such as fibromyalgia and myofascial pain), and pain associated with disease or medical procedures.
Improving synaptic plasticity, hippocampal long-term potentiation, cognition, and memory or learning in patients with neurological dysfunction.
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