Compositions and methods for treating neurodegenerative diseases
Inventors
Assignees
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Publication Number
US-10364236-B2
Publication Date
2019-07-30
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 invention relates to unit dose compounds defined by formulae (I) or (II), including pharmaceutically acceptable salts, for treating Huntington’s Disease in a human. The unit dose comprises about 80 mg to about 700 mg total of one or more compounds of the formulae, with defined substituent selections for A/A′, R1–R5, n, stereochemical options, and, depending on the formula, Q being oxygen or sulfur or disulfide and related oxidized derivatives.
A core feature is that the compounds are selective for the V1a receptor compared to the V1b receptor by a factor of about 10 or greater. The description further supports V1a binding and functional antagonism using receptor assays and selectivity comparisons, including competitive binding and functional inhibition of phosphatidylinositol turnover.
The therapy is linked to neuropsychiatric symptom domains such as aggression, irritability, anger, depression, and anxiety, with decreased BOLD responses in emotion and threat regions and improvement in neuropsychiatric symptom measures. The disclosure also indicates limited or no effects on sexual behavior and mentions optional prophylactic or delaying effects related to later movement disorder onset.
Claims Coverage
The consolidated claim coverage centers on a unit dose composition defined by formulae (I) and (II) with specific chemical variables and a V1a selectivity requirement over V1b by about 10 or greater, adapted for treating Huntington’s Disease in a human.
Parameterized unit dose composition with formulae (I) and (II)
A unit dose comprising about 80 mg to about 700 mg total of one or more compounds of the formulae (I) and/or (II) or a salt thereof, with A and A′ selected from —C(O)2H, or an ester or amide derivative thereof; n selected from integers 0 to about 3 or 1 to 3 depending on the formula context; R1 selected from hydrogen or C1–C6 alkyl; R2, R3, and R4 selected according to defined substituent groups; and, for formula (II), Q is oxygen or sulfur or disulfide or an oxidized derivative thereof with R5″ defined as a specified set of substituent options.
Huntington’s Disease treatment in a human
The unit dose is adapted for treating Huntington’s Disease in a human.
V1a receptor selectivity over V1b by about 10 or greater
The one or more compounds are selective for the V1a receptor compared to the V1b receptor by a factor of about 10 or greater.
The independent claim coverage requires a unit dose defined by formulae (I) and (II) with specified structural variables, adapted for Huntington’s Disease treatment, and constrained by V1a selectivity over V1b by about 10 or greater.
Stated Advantages
Selective compounds for the V1a receptor compared to the V1b receptor by a factor of about 10 or greater for treating Huntington’s Disease in a human.
Decreased BOLD responses in emotion and threat regions.
Improvement in neuropsychiatric symptom measures.
Limited or no effects on sexual behavior.
Documented Applications
Treatment of Huntington’s Disease in a human.
Treating Huntington’s Disease, Parkinson’s Disease, and Alzheimer’s Disease with neuropsychiatric aspects such as aggression, irritability, anger, depression, and anxiety.
Treating or addressing neuropsychiatric symptoms including aggression, irritability, and anger.
Optional prophylactic or delaying of later movement disorder onset.
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