Isoindoline compositions and methods for treating neurodegenerative disease
Inventors
Rishton, Gilbert M. • Catalano, Susan M. • Look, Gary C.
Assignees
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Publication Number
US-11691947-B2
Publication Date
2023-07-04
Expiration Date
Abstract
Isoindoline sigma-2 receptor antagonist compounds, pharmaceutical compositions comprising such compounds, and methods for inhibiting Abeta-associated synapse loss or synaptic dysfunction in neuronal cells, modulating an Abeta-associated membrane trafficking change in neuronal cells, and treating cognitive decline associated with Abeta pathology are provided.
Core Innovation
The invention relates to sigma-2 receptor-binding isoindoline compounds of Formula I, Formula II, and Formula III, including compounds and pharmaceutically acceptable salts, carriers, and excipients. The compounds are defined with broad substituent groups associated with the isoindoline core, including allowed functional groups and ring-forming or linking options, and representative compound embodiments are provided by detailed chemical structures.
The disclosure addresses neurodegenerative disease and cognitive decline associated with amyloid-beta pathology, including Alzheimer's disease and early-stage Alzheimer's disease. The compounds are linked to inhibiting amyloid-beta oligomer-induced synapse loss and synapse dysfunction, inhibiting amyloid-beta oligomer binding, and modulating amyloid-beta-associated membrane trafficking changes in neuronal cells, with preferential sigma-2 receptor binding and selectivity versus sigma-1.
The treatment methods frame administration of sigma-2 receptor-binding isoindoline compounds or pharmaceutically acceptable salts within specified dosing ranges, and the disclosure includes pharmaceutical compositions using pharmaceutically acceptable carriers or excipients. The compounds are also described as functional antagonists associated with preservation of neuronal structure and viability under amyloid-beta oligomer exposure and with therapeutic outcomes in Alzheimer's disease.
Claims Coverage
The independent claims cover methods of treating Alzheimer's disease by administering a Formula compound or pharmaceutically acceptable salt, either directly or as a pharmaceutical composition including a pharmaceutically acceptable carrier or excipient. The stated daily dose range is about 0.01 mg/kg/day to about 25 mg/kg/day, and the claims present two core inventive features.
Formula compound administration for Alzheimer's disease treatment
Administering to a subject having Alzheimer's disease a dose of about 0.01 mg/kg/day to about 25 mg/kg/day of a compound of the Formula, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier or excipient for Alzheimer's disease treatment
Administering to a subject having Alzheimer's disease a pharmaceutical composition comprising a compound of the Formula, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, wherein a dose of the compound or pharmaceutically acceptable salt thereof is administered within about 0.01 mg/kg/day to about 25 mg/kg/day.
Across the independent claims, the core coverage is treating Alzheimer's disease by administering a Formula-based compound or pharmaceutically acceptable salt at about 0.01 mg/kg/day to about 25 mg/kg/day, with one claim limited to the compound itself and the other requiring a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient.
Stated Advantages
Inhibits amyloid beta (Aβ) effects on neuronal cells, including Aβ oligomer binding, Aβ oligomer-induced synapse loss, synapse dysfunction, and membrane trafficking deficits.
Reduces or prevents cognitive decline, including mild cognitive impairment and early Alzheimer's disease.
Shows preferential sigma-2 receptor binding/selectivity versus sigma-1.
Provides high sigma-2 affinity, functional antagonism of amyloid-beta oligomer-induced effects, brain penetrability, and stability.
Documented Applications
Treatment of Alzheimer's disease by administering the described compounds or pharmaceutical compositions to a subject having Alzheimer's disease.
Inhibition of amyloid beta (Aβ) effects on neuronal cells, including inhibiting Aβ oligomer binding and preventing Aβ oligomer-induced synapse loss and membrane trafficking deficits.
Assessment in Alzheimer's disease-related transgenic models, human Alzheimer's disease patient-derived oligomers, and neuronal assays, with behavioral efficacy examples referenced.
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