Isoindoline compositions and methods for treating neurodegenerative disease
Inventors
Rishton, Gilbert • Catalano, Susan M. • Look, Gary C.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9796672-B2
Publication Date
2017-10-24
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 selective sigma-2 receptor antagonist compounds provided as compounds of Formula I, Formula II, and Formula III, including isoindoline sigma-2 receptor antagonist compounds and pharmaceutically acceptable salts thereof. The compounds include broad substituent definitions and illustrated structures, with specific embodiments including fumarate and hydrochloride salt forms, stereoisomers, and selected compound species.
The described compounds are intended to inhibit amyloid beta effects on neuronal cells, neurons, and synapses. The disclosed amyloid beta effect includes inhibition of amyloid beta oligomer binding, membrane trafficking abnormalities, synapse number decline, synapse loss, suppression of long term potentiation, and oligomer-mediated cognitive effects.
Pharmaceutical compositions are described as comprising the defined compounds or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier or excipient. The disclosure also states administering an effective amount to a subject in need thereof for inhibiting amyloid beta effects on neuronal cells and for treating Alzheimer’s disease, including cognitive decline and mild cognitive impairment.
Claims Coverage
The independent claims cover four principal inventive aspects: selective sigma-2 receptor antagonist compounds defined by Formula I, Formula II, or Formula III, pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier or excipient, methods for inhibiting amyloid beta effects on neuronal cells, and methods for treating Alzheimer’s disease. Dependent refinements emphasize specific salt selection, including fumarate and hydrochloride, and associate the amyloid beta effect with cognitive decline, cognitive impairment, and mild cognitive impairment in Alzheimer’s disease.
Sigma-2 receptor antagonist compound of formula and pharmaceutically acceptable salt
A compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, including refinements to specific salt forms such as fumarate or hydrochloride.
Pharmaceutical composition with carrier or excipient
A composition comprising a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Inhibiting amyloid beta effect on a neuronal cell by administration
A method for inhibiting amyloid beta effect on a neuronal cell comprising administering to a subject in need thereof an effective amount of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof.
Treating Alzheimer’s disease by administering an effective amount
A method of treating Alzheimer’s disease by administering an effective amount of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, to a subject.
Overall, the claim coverage centers on selective sigma-2 receptor antagonist compounds defined by the claimed formulas and their pharmaceutically acceptable salts, pharmaceutical compositions containing those compounds, and administration-based methods directed to inhibiting amyloid beta effects on neuronal cells and treating Alzheimer’s disease.
Stated Advantages
Inhibits amyloid beta oligomer binding.
Reduces synapse number decline and synapse loss.
Inhibits amyloid beta-induced membrane trafficking abnormalities and membrane trafficking deficits.
Suppresses long term potentiation suppression.
Inhibits soluble amyloid beta oligomer-mediated cognitive effects, including cognitive decline, learning deficits, cognitive impairment, and mild cognitive impairment in Alzheimer’s disease.
Reversal of Morris swim and fear-conditioning related memory loss in transgenic Alzheimer’s mouse models.
Reduces Abeta-induced cellular toxicity by competition with Abeta oligomers.
Modulates neuronal membrane trafficking changes associated with Abeta.
Documented Applications
Pharmaceutical compositions comprising the defined compounds or pharmaceutically acceptable salts with pharmaceutically acceptable carriers or excipients.
Methods for inhibiting amyloid beta effects on neuronal cells by administering an effective amount of the defined compounds or pharmaceutically acceptable salts to subjects in need.
Treating Alzheimer’s disease, including cognitive decline and mild cognitive impairment, by administering an effective amount of the defined compounds or pharmaceutically acceptable salts.
Reversal of memory loss in transgenic Alzheimer’s mouse models using Morris swim and fear-conditioning readouts.
Inhibition of Abeta oligomer-induced membrane trafficking/exocytosis changes.
Use in a binding/synapse loss context using Abeta1-42 oligomer binding quantified by immunohistochemistry and image analysis and synaptophysin puncta.
Characterization of sigma-2/sigma-1 distribution and antagonist/agonist activity, including viability and caspase-3 activity profiling.
Pharmacokinetic/metabolic stability evaluation to relate metabolic stability, half-life, and brain penetrability.
Inhibiting long term potentiation suppression associated with Abeta pathology.
Suppressing cognitive decline and mild cognitive impairment in Alzheimer’s disease.
Interested in licensing this patent?