GluN2B-subunit selective antagonists of the N-methyl-D-aspartate receptors with enhanced potency at acidic pH
Inventors
Liotta, Dennis • Traynelis, Stephen • Wilson, Lawrence • Tahirovic, Yesim Altas • MENALDINO, David • Myers, Scott • Poornachary, Kamalesh
Assignees
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Publication Number
US-12415790-B2
Publication Date
2025-09-16
Expiration Date
Abstract
Compounds that selectively inhibit GluN2B-containing N-methyl-D-aspartic acid receptors (NM/DARs) are disclosed. In some cases, the compounds selectively target GluN2B over GluN2A, GluN2C, and/or GluN2D. Generally, the compounds possess an enhanced potency to GluN2B at a pH that is more acidic compared to the physiological pH. Pharmaceutical formulations containing one or more of the compounds are also disclosed. Additionally, methods of treating a condition, disorder or disease using the compounds or their pharmaceutical formulations thereof are disclosed. Exemplary conditions, disorders, and diseases relevant to this disclosure include stroke, subarachnoid hemorrhage, cerebral ischemia, cerebral vasospasm, hypoxia, acute CNS injury, spinal cord injury, traumatic brain injury, coronary artery bypass graft, persistent or chronic cough, substance abuse disorder, opiate withdrawal, opiate tolerance, bipolar disorder, suicidal ideation, pain, fibromyalgia, depression, postpartum depression, resting tremor, dementia, epilepsy, seizure disorder, movement disorder, and neurodegenerative disease.
Core Innovation
The invention relates to GluN2B-subunit selective negative allosteric modulators of N-methyl-D-aspartate receptors (NMDAR). The compounds are described by Formula I, Formula II, Formula IA, Formula IIA, and related variants, including stereochemistry at a labeled chiral center where the stereocenter has an R configuration.
The subject matter includes the compound itself and pharmaceutically acceptable salts, hydrates, hydrated salts, and free-base form. The disclosure further addresses R-enantioenriched compositions by defining enantiomeric excess levels relative to the S enantiomer, and describes pharmaceutical composition forms with standard dosage forms and routes, including oral and intravenous formulation.
A key concept is pH-dependent potency for GluN2B, with enhanced potency at acidic pH relative to physiological pH and a pH boost metric evaluated by IC50 comparison at different pH values. The disclosure connects this pH sensitivity to extracellular acidification and GluN2B negative allosteric NMDAR modulator activity, and discusses associated conditions and indications such as stroke, subarachnoid hemorrhage, cerebral ischemia, hypoxia, acute CNS injury, pain, depression, dementia, epilepsy, neurodegenerative disease, and COVID-19-associated respiratory insufficiency and/or prolonged ventilator use.
Claims Coverage
The independent claim family covers a structure-defined compound and pharmaceutically acceptable salts, hydrates, and hydrated salts. Dependent claims further add stereochemical enantiomeric-excess constraints, pharmaceutical formulations with pharmaceutically acceptable excipients, dosage forms and administration routes, and treatment methods for selected conditions including a COVID-19-associated respiratory insufficiency and/or prolonged ventilator use limitation.
Formula-defined compound with pharmaceutically acceptable salt forms
A compound having a structure as defined, or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof.
R-enantioenriched composition relative to S enantiomer
A composition containing the compound, wherein the composition is specified to have greater than 80%, 85%, 90%, or 95% enantiomeric excess relative to the S enantiomer.
Pharmaceutical formulation with pharmaceutically acceptable excipient
A pharmaceutical formulation that includes the compound and additionally contains a pharmaceutically acceptable excipient.
Dosage form pharmaceutical formulations and packaging/instructions features
A pharmaceutical formulation specified to be in dosage forms including tablets/capsules and other oral or intravenous forms, including lyophilized powder and sterile aqueous solution, optionally with single-dose or multi-dose holders and product information and/or instructions for use.
Treatment method using an effective amount by oral or intravenous administration
A method for treating a selected condition or disorder in a subject by administering an effective amount of a composition, with optional oral or intravenous administration of the pharmaceutical formulation.
COVID-19-associated respiratory insufficiency and/or prolonged ventilator use association
The method wherein the respiratory insufficiency and/or prolonged ventilator use is associated with COVID-19.
Overall, the claim coverage centers on a structure-defined compound, extends to R-enantioenriched compositions with explicit enantiomeric-excess thresholds, and further includes pharmaceutical formulations and treatment methods for a range of conditions, including a COVID-19-associated respiratory insufficiency and/or prolonged ventilator-use association.
Stated Advantages
Enhanced potency at acidic pH versus physiological pH.
pH-dependent potency for GluN2B, with R enantiomers exhibiting higher or comparable pH boost versus S based on IC50 at pH 6.9 versus pH 7.6.
Documented Applications
Treatment of stroke.
Treatment of subarachnoid hemorrhage.
Treatment of cerebral ischemia.
Treatment of cerebral vasospasm.
Treatment related to hypoxia.
Treatment of acute CNS injury.
Treatment of spinal cord injury.
Treatment of traumatic brain injury.
Treatment related to a condition involving respiratory insufficiency and/or prolonged ventilator use associated with COVID-19.
Treatment of persistent or chronic cough.
Treatment of substance abuse disorder.
Treatment of opiate withdrawal.
Treatment of opiate tolerance.
Treatment of bipolar disorder.
Treatment of suicidal ideation.
Treatment of pain.
Treatment of fibromyalgia.
Treatment of depression.
Treatment of postpartum depression.
Treatment of resting tremor.
Treatment of dementia.
Treatment of epilepsy.
Treatment of seizure disorder.
Treatment of movement disorder.
Treatment of neurodegenerative disease.
Treating conditions or disorders including stroke, subarachnoid hemorrhage, cerebral ischemia, hypoxia, acute CNS injury, pain, depression, dementia, epilepsy, and neurodegenerative disease, as part of a method of administering an effective amount.
Treating COVID-19-associated respiratory insufficiency and/or prolonged ventilator use by the claimed method.
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