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-10611728-B2
Publication Date
2020-04-07
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 provides selective sigma-2 receptor antagonist isoindoline compounds defined by Formula I, Formula II, and Formula III, including embodiments with substituent definitions, pharmaceutically acceptable salts, racemates, enantiomers, and specific chemical structures and example compounds. The disclosure also includes excluded compounds, substituted aromatic and heterocyclic motifs, and compound members identified by structural representations and characterization data.
The compounds are described in connection with amyloid beta effects on neuronal cells, including inhibition of amyloid beta oligomer binding, inhibition of amyloid beta oligomer-induced membrane trafficking deficits, synapse loss, synaptic dysfunction, and soluble amyloid beta oligomer-mediated cognitive effects. The document further characterizes antagonism at sigma-2 and modulation of downstream signaling, together with assay evidence and in vivo behavioral efficacy in transgenic AD models.
The described compositions and treatment methods target Alzheimer's disease by administering the selective sigma-2 receptor antagonist compounds, or pharmaceutically acceptable salts thereof, at a total daily dose of 10 to 2000 mg. In some embodiments, the compounds are provided in pharmaceutical compositions with pharmaceutically acceptable carriers or excipients, and the composition may be provided as a capsule or a tablet.
Claims Coverage
The consolidated claim coverage identifies two independent claim types: one directed to treating Alzheimer's disease by administering a compound of the stated Formula, or a pharmaceutically acceptable salt thereof, and the other directed to treating Alzheimer's disease by administering a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient. Across the inputs, the common inventive framework is a total daily dose range of 10 to 2000 mg, with dependent refinements to compound selection, dose sub-ranges, dosing regimen, route, and dosage form.
Treating Alzheimer's disease by administering a formula compound
Administering to a subject having Alzheimer's disease a total daily dose of 10 to 2000 mg of a compound of the Formula, or a pharmaceutically acceptable salt thereof.
Treating Alzheimer's disease with a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier or excipient
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 the total daily dose of the compound administered is 10 to 2000 mg.
Specified compound members by chemical structure identifiers
Selecting the compound as a specific chemical structure shown in the disclosure, including embedded chemical identifiers and excluded structures.
Narrowed dosing regimen and dosage form
Dependent claims further refine administration by route, single dose or multiple doses per day, dose sub-ranges, and capsule or tablet dosage forms.
Overall, the claim set centers on treating Alzheimer's disease using selective sigma-2 receptor antagonist compounds defined by the stated Formulae, or pharmaceutically acceptable salts, at a total daily dose of 10 to 2000 mg. The coverage also includes pharmaceutical composition embodiments with a carrier or excipient, and dependent features that narrow compound identity, dosing regimen, and dosage form.
Stated Advantages
Inhibits amyloid beta oligomer binding.
Inhibits amyloid beta oligomer-induced membrane trafficking deficits, synapse loss, synaptic dysfunction, and soluble amyloid beta oligomer-mediated cognitive effects.
Inhibits amyloid-beta oligomer-induced membrane trafficking deficits.
Inhibits synapse loss.
Inhibits non-lethal amyloid-beta pathology.
Suppresses amyloid-beta oligomer-related disruption of hippocampal long-term potentiation.
Provides in vivo behavioral efficacy in transgenic AD models, including memory improvement in the Morris swim test.
Brain penetrability and plasma and metabolic stability are emphasized as part of the compound profile.
Documented Applications
In vitro and in cell inhibition of amyloid beta effects on neuronal cells.
Treating Alzheimer's disease by administering a selective sigma-2 receptor antagonist compound, or a pharmaceutically acceptable salt thereof, within the claimed total daily dose range.
Treating Alzheimer's disease by administering a compound of the Formula, or a pharmaceutically acceptable salt thereof, including administration as a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient.
Treating cognitive decline and mild cognitive impairment in Alzheimer's disease.
Use in transgenic AD models, including behavioral efficacy assessed by memory improvement in the Morris swim test.
Inhibiting amyloid beta effects on neuronal cells by administering pharmaceutical compositions containing compounds of Formula II (or pharmaceutically acceptable salts) under substituent-defined embodiments.
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