Compositions and methods for treating neurodegenerative diseases
Inventors
Assignees
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Publication Number
US-9802925-B2
Publication Date
2017-10-31
Expiration Date
Abstract
Compounds, and compositions, methods, and uses thereof, are described herein for treating neurodegenerative diseases and disorders. In particular, vasopressin receptor modulators, and compositions, methods and uses thereof, are described herein for treating neuropsychiatric aspects of neurodegenerative diseases such as Huntington's Disease, Parkinson's Disease, and Alzheimer's Disease.
Core Innovation
The disclosure provides selective vasopressin V1a receptor antagonists defined by a detailed chemical formula and pharmaceutically acceptable salts. A composition comprising one or more selective vasopressin V1a receptor antagonists is administered to a host animal, where at least one antagonist is a compound of the formula or a salt thereof. The invention is directed to treating Huntington’s Disease, Parkinson’s Disease, or Alzheimer’s Disease.
The formula characterizes multiple variable groups, including A, B, R1, R2, R3, and R4, each having defined chemical options and substituent selections. A and B are carboxylic acid, ester, or amide, with B also described as an alcohol or thiol or a derivative thereof. R1 is hydrogen or C1-C6 alkyl, R2 is hydrogen or various groups including —CO2R8, —CONR8R8′, and —NR8(COR9), R3 is an amino, amido, acylamido, or ureido group or a nitrogen-containing heterocyclyl group attached at a nitrogen atom, and R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, or optionally substituted aryl and arylalkyl variants.
The disclosure frames the therapeutic approach around excessive vasopressin V1a receptor signaling in neurocircuitry and selective attenuation of AVP-induced signaling relative to V1b and V2 receptor activity. The compounds are supported by receptor-level and functional pharmacology characterization, including competitive binding assays at human V1a and V1b receptors and functional assays using phosphatidylinositol/IP3 turnover to classify compounds as V1a antagonists.
Claims Coverage
The provided set includes one independent claim. The main claim coverage centers on administering selective vasopressin V1a receptor antagonists for treating Huntington’s Disease, Parkinson’s Disease, or Alzheimer’s Disease, with the antagonist chemical scope defined by a specific formula and substituent definitions.
Treating Huntington’s disease, Parkinson’s disease, or Alzheimer’s disease with selective vasopressin V1a receptor antagonists
A method for treating Huntington’s Disease, Parkinson’s Disease, or Alzheimer’s Disease in a host animal by administering a composition comprising one or more selective vasopressin V1a receptor antagonists, where at least one antagonist is a compound of the formula or a salt thereof.
Constrained antagonist scaffold with specified variable substituent definitions
At least one antagonist is a compound of the formula or a pharmaceutically acceptable salt thereof, with A and B selected from stated carboxylic acid, ester, or amide derivative options, R1, R2, R3, and R4 defined as specified, including the stated conditions for R8, R8′, and R9 options.
Pharmaceutical composition for neurodegenerative disease treatment
A pharmaceutical composition containing one or more compounds of the formula, optionally with carriers, diluents, and/or adjuvants, is adapted or capable of treating a neurodegenerative disease or disorder in a host animal.
Neuropsychiatric symptoms including aggression, irritability, or anger
The method is characterized by neuropsychiatric symptoms that include aggression, irritability, or anger, or any combination of these.
Neuropsychiatric symptom targeting in Alzheimer’s disease
The method treats one or more neuropsychiatric symptoms of Alzheimer’s disease.
Overall, claim coverage centers on administering a composition containing selective vasopressin V1a receptor antagonists for treatment of Huntington’s Disease, Parkinson’s Disease, or Alzheimer’s Disease, with at least one antagonist selected from compounds or salts defined by a comprehensive set of substituent-variable definitions for A, B, R1, R2, R3, and R4.
Stated Advantages
CNS-penetrant oral activity and BBB crossing (CNS activity is emphasized).
V1a selectivity versus V1b/V2 (selective vasopressin V1a receptor antagonism).
Treatment, prophylaxis, or delaying movement disorder onset.
Targeting neuropsychiatric symptoms, including aggression, irritability, anger, and BPSD.
Addresses an unmet need due to failures of existing psychiatric drugs.
Attenuates excessive AVP/V1a-driven signaling in emotion/threat circuitry as shown by fMRI BOLD response attenuation.
Provides selective vasopressin V1a antagonism supported by competitive binding and functional IP3/PI turnover characterization.
Documented Applications
Treating neuropsychiatric symptoms of Alzheimer’s disease, including aggression, irritability, anger, or combinations.
Treating behavioral and psychological symptoms in dementia (BPSD) within the neurodegenerative disease treatment context.
Treating Huntington’s Disease and Parkinson’s Disease in a host animal with selective vasopressin V1a receptor antagonists.
Treating Huntington’s Disease in a host animal by administering selective vasopressin V1a receptor antagonists.
Treating Parkinson’s Disease in a host animal by administering selective vasopressin V1a receptor antagonists.
Treating Alzheimer’s Disease in a host animal by administering selective vasopressin V1a receptor antagonists.
Narrowing neuropsychiatric symptoms in Alzheimer’s disease (one or more neuropsychiatric symptoms) treated in the host.
Narrowing neuropsychiatric symptoms that include aggression, irritability, or anger, or combinations thereof.
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