Compositions and methods for treating brain injury
Inventors
Assignees
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Publication Number
US-11628160-B2
Publication Date
2023-04-18
Expiration Date
Abstract
Compounds, and compositions, methods, and uses thereof, are described herein for treating brain injuries.
Core Innovation
The invention relates to treating traumatic brain injury in a host animal by administering a compound selected from a group of selective arginine vasopressin V1a receptor (V1aR) antagonist compounds, and combinations thereof, including salts of any of the foregoing. The approach targets AVP/V1aR because of effects on cerebral vascular resistance and brain water permeability that are relevant to cerebral edema and secondary injury. The invention supports systemic administration feasibility, including oral administration, while avoiding clinically significant blood pressure or cardiovascular adverse effects.
The disclosed compound class includes chiral, substituted β-lactam/azetidin-2-one derivatives derived from amino-acid derivatives such as D-aspartic acid and L-glutamic acid via imine formation and 2+2 cycloaddition. The resulting stereochemical assignments are handled through labels such as 3S/4R, (R), (S), and not determined. The invention includes pharmaceutical compositions and medicaments, and representative compound scaffolds are defined by formulas I and II using substituent variables and stereochemistry.
The document further describes downstream modifications of the β-lactam/azetidin-2-one derivatives, including acylation, ester hydrolysis to carboxylic acids, and N-oxide formation. Named representative compounds include AVN228, AVN246, AVN251, AVN296, and AVN576. The invention also connects the disclosed compound set to treatment of traumatic brain injury types and conditions including blast TBI, repeated mild TBI, cerebral edema, chronic traumatic encephalopathy, subarachnoid hemorrhage, stroke, concussion, falls, and related endpoints such as edema, cognitive/learning/memory and motor deficits.
Claims Coverage
The independent claim covers a method for treating traumatic brain injury in a host animal by administering a compound selected from a group of compounds, including combinations thereof, and salts of any of the foregoing. The provided claim coverage includes 8 inventive features, combining the selective V1aR antagonist compound administration with dependent claims narrowing the traumatic brain injury scope to specific types and related conditions.
Treating traumatic brain injury by administering a selective V1aR antagonist compound
A method for treating a traumatic brain injury in a host animal comprising administering to the host animal a compound selected from the group consisting of the selective V1aR antagonist compounds, including combinations thereof, and salts of any of the foregoing.
Treating traumatic brain injury by administering a selected compound to a host animal
A method for treating a traumatic brain injury in a host animal by administering to the host animal a compound selected from the group consisting of compounds, and combinations thereof, and salts of any of the foregoing.
Traumatic brain injury including blast tbi
The method of treating traumatic brain injury includes blast TBI.
Traumatic brain injury including repeated mild tbi
The method of treating traumatic brain injury includes repeated mild TBI (rmTBI).
Traumatic brain injury including cerebral edema
The method of treating traumatic brain injury is characterized in that the traumatic brain injury includes cerebral edema.
Traumatic brain injury including chronic traumatic encephalopathy
The method is for traumatic brain injury (TBI) that includes chronic traumatic encephalopathy.
Traumatic brain injury including subarachnoid hemorrhage
The method is for traumatic brain injury (TBI) that includes subarachnoid hemorrhage.
Traumatic brain injury including concussion
The method of treating traumatic brain injury includes concussion.
Claim coverage centers on administering selected compounds and salts to treat traumatic brain injury in a host animal, with dependent claims narrowing the traumatic brain injury scope to specific conditions including blast TBI, repeated mild TBI (rmTBI), cerebral edema, chronic traumatic encephalopathy, subarachnoid hemorrhage, and concussion.
Stated Advantages
Avoids clinically significant blood pressure/cardiovascular adverse effects while enabling systemic administration, including oral administration.
Targets AVP/V1aR effects on cerebral vascular resistance and brain water permeability relevant to cerebral edema and secondary injury.
Prevents cognitive/learning/memory deficits after traumatic brain injury.
Reduces cerebral edema.
Restores ventricular volumes.
Normalizes/restores resting-state functional connectivity after injury.
Documented Applications
Treatment of traumatic brain injury in a host animal, including blast traumatic brain injury, repeated mild traumatic brain injury, cerebral edema, chronic traumatic encephalopathy, subarachnoid hemorrhage, stroke, concussion, and falls, using a vasopressin receptor antagonist regimen.
Use of controlled cortical impact and momentum-exchange concussion models as traumatic brain injury and concussion-related applications, with MRI approaches including T2 relaxometry and resting-state fMRI, and behavioral assays to evaluate outcomes.
Treatment of traumatic brain injury in a host animal by administering a compound selected from a group of compounds and combinations thereof, including salts of any of the foregoing.
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