Compounds and methods for treating neurological and cardiovascular conditions
Inventors
Korinek, William S. • Lechleiter, James D. • Liston, Theodore E.
Assignees
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Publication Number
US-12390483-B2
Publication Date
2025-08-19
Expiration Date
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 treating a brain or central nervous system (CNS) injury or condition by administering to a patient in need an effective amount of a compound selected from (N)-methanocarba nucleoside derivatives, A3 adenosine receptor agonist compounds, biased agonists, partial agonists, and related agents, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof. The disclosed subject matter includes methanocarba nucleoside stereochemical conformation concepts, representative C3′-endo/C2′-exo and C3′-exo/C2′-endo conformations, and purine-like scaffolds, phosphate forms, and pharmaceutically acceptable salts as receptor-ligand candidates.
The patent describes purinergic receptor modulation, primarily via adenosine A3 receptor (A3R) signaling, with optional P2Y1 receptor involvement, as a platform for neuroprotective and neurorestorative effects. The disclosure includes functionally selective, biased pathway modulation with cAMP accumulation and related receptor-mediated signaling readouts, together with A3R pathway-biased modulation associated with β-arrestin recruitment partial agonism and Gq/11-mediated Ca2+ mobilization.
Representative embodiments include compounds such as MRS4322 and MRS1873, and the documented context indicates biased or partial agonist activity at the human A3R. The disclosure also identifies exposure-related considerations such as unbound fraction in plasma and unbound fraction in brain, blood-brain barrier penetration supported by brain/plasma ratios, and an improved physicochemical profile versus low-solubility prototypical A3 agonists, including lower cLogP and higher unbound fractions in plasma and the brain.
Claims Coverage
The consolidated claim coverage includes one independent claim directed to treating a brain or CNS injury or condition by administering an effective amount of a selected compound, with three core inventive features recurring across the inputs. Dependent refinements add the listed condition scope, neuroprotection or neurorestoration comparisons, a recovery period change, a within-48-hours-after-stroke administration window, and comparative outcomes versus an untreated patient.
Treating brain or cns injury by administering a selected compound
A method of treating a brain or central nervous system (CNS) injury or condition by administering to a patient in need thereof an effective amount of a compound selected from the disclosed group, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.
Targeting specified brain or cns injury and condition types
The brain or CNS injury or condition is selected from radiation damage, migraine headache, ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, or transient ischemic attacks (TIA).
Neuroprotection or neurorestoration increase compared with an untreated patient
Increasing neuroprotection or neurorestoration in the patient as compared with an untreated patient, with dependent claim refinements stating that this decreases the recovery period after cerebrovascular events.
Administration within 48 hours after stroke
The compound, salt, or composition is administered within 48 hours after the stroke.
Overall, the inventive coverage centers on administration of a selected compound for treatment of the listed brain or CNS injuries and conditions, with refinements tied to neuroprotection or neurorestoration, decreased recovery period versus an untreated patient, and administration within 48 hours after stroke.
Stated Advantages
Increases neuroprotection or neurorestoration as compared with an untreated patient.
Decreases the recovery period after cerebrovascular events as compared with an untreated patient.
Reduces infarct size at 24 h, as measured by TTC staining.
A3R antagonism with MRS1523 abolishes the neuroprotective effect of MRS4322 and MRS2365 (and MRS5698).
Comparable efficacy and pharmacokinetics are noted for the 2-chloro analog MRS1873 versus MRS4322.
Improved physicochemical profile versus low-solubility prototypical A3 agonists, including lower cLogP and higher unbound fractions in plasma and the brain.
Blood-brain barrier penetration is supported by brain/plasma ratios.
Documented Applications
Treatment of a brain or central nervous system (CNS) injury or condition, including radiation damage, migraine headache, ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, cerebral vasospasm, and transient ischemic attacks (TIA).
Stroke-related treatment embodiments in which the compound is administered within 48 hours after the stroke.
Therapeutic use for brain injury or neurodegenerative disease via pathway-biased A3R modulation.
In vivo stroke study design in mice using photothrombosis-induced stroke to test neuroprotective efficacy of MRS4322 and MRS2365, with comparisons involving A3R antagonism and full A3R agonists.
A related example using a similar stroke model to evaluate the 2-chloro analog MRS1873 versus MRS4322.
Cardioprotection in connection with cardiac ischemia and myocardial infarction.
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