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-12466795-B2
Publication Date
2025-11-11
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 disclosure describes pharmaceutical composition embodiments comprising a compound of a specified Formula, including Formula I, Formula II, and Formula III embodiments, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. The compositions are characterized by a compound amount in the range of 10 to 2000 mg, with narrower amounts including 10 to 300 mg and 20 to 150 mg, and by oral delivery and capsule or tablet dosage forms.
The disclosed content describes sigma-2 receptor antagonist compounds and relates to inhibition of amyloid beta effects on neuronal cells, including amyloid beta oligomer binding, synapse loss, membrane trafficking deficits, and cognitive decline. The disclosure links sigma-2 targeting to treatment of neurodegenerative disease, including Alzheimer’s disease and mild cognitive impairment, and includes contexts such as primary hippocampal neurons and related imaging and quantification.
The input also describes example compound structures and characterization data for isoindoline or isoindoline-like compounds, including salt forms such as hydrochloride salts, with 1H NMR, ESI+ MS, and mass spectrometry confirmation. The examples include structural variants with fluorine, trifluoromethoxy, methoxy, carboxylic acid, ester, sulfonamide, and sulfone motifs, and the reported structures and peak assignments are used to confirm compound identity.
Claims Coverage
The consolidated claim coverage centers on one pharmaceutical composition claim family. Across the provided independent-claim content, there are 2 inventive features: a defined Formula compound in a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and a specified compound amount range in the composition, with dependent claims narrowing dosage and formulation form.
Pharmaceutical composition with defined Formula compound and pharmaceutically acceptable carrier or excipient
A pharmaceutical composition comprising 10 to 2000 mg of a compound of the Formula, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Narrowed compound amount range
Dependent embodiments specify 10 to 300 mg of the compound or 20 to 150 mg of the compound.
Oral delivery formulation
The pharmaceutical composition is formulated for oral delivery.
Capsule or tablet dosage form
The pharmaceutical composition is provided in a capsule or tablet dosage form.
Compound defined by provided chemical structure representations
The pharmaceutical composition includes a compound represented by the provided chemical structure images/files.
The claim coverage is directed to a pharmaceutical composition containing a Formula compound, or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable carrier or excipient, with dependent claims further defining the amount range, oral delivery, capsule or tablet dosage form, and compound identification by embedded structure representations.
Stated Advantages
Inhibits amyloid beta effects.
Inhibits amyloid beta oligomer binding on neuronal cells.
Suppresses membrane trafficking deficits.
Suppresses LTP suppression and restores synaptic function to pre-exposure levels.
Treats cognitive decline, including mild cognitive impairment, in Alzheimer’s disease.
Inhibiting amyloid beta effects on neuronal cells, including amyloid beta oligomer binding and associated functional deficits.
Addressing synapse loss and membrane trafficking deficits associated with amyloid beta oligomer binding.
Treating cognitive decline and/or neurodegenerative disease, including Alzheimer’s disease and mild cognitive impairment.
Documented Applications
Pharmaceutical compositions intended to inhibit amyloid beta effects, including inhibition of amyloid beta oligomer binding on neuronal cells.
Treatment of cognitive decline and mild cognitive impairment in Alzheimer’s disease.
In vitro and in vivo testing using Aβ 1-42 oligomers as positive controls to evaluate counteraction of Aβ oligomer-induced neuronal membrane trafficking deficits.
Screening in primary neuronal cultures using functional readouts including exocytosis and membrane trafficking.
Assays described for Aβ oligomer binding/synapse loss and fear conditioning behavioral efficacy.
Sigma receptor autoradiography and characterization of sigma-2 ligands as agonists/antagonists, including cell viability and caspase-3 activity.
Treatment of neurodegenerative diseases including Alzheimer’s disease.
Use in fear conditioning assay and Morris water maze contexts.
Inhibition of amyloid beta effects in neuronal cells.
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