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-10207991-B2
Publication Date
2019-02-19
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 relates to selective sigma-2 receptor antagonist compounds of Formula I and Formula II, including isoindoline compounds and related selected embodiments, each optionally in the form of a pharmaceutically acceptable salt. The compounds are defined by substituent-variable groups R1 through R11 with permitted substituent types, optional linking into specified ring systems, and an O-C1-2 methylene-O group in some embodiments.
The disclosed compounds are presented as selective sigma-2 receptor ligands with functional antagonist activity and are associated with inhibiting amyloid beta effects on neuronal cells and synapses. The text describes interference with amyloid beta oligomer binding to neurons and synapses, prevention of non-lethal amyloid beta pathology, inhibition of amyloid beta-associated synapse loss or dysfunction, membrane trafficking defects, exocytosis or membrane trafficking deficits, and synaptic dysfunction decline.
The disclosure further includes pharmaceutical compositions and methods using an effective amount of a compound and a pharmaceutically acceptable carrier or excipient to inhibit amyloid beta effects on neuronal cells. The therapeutic context includes Alzheimer’s disease, cognitive decline, cognitive impairment, and mild cognitive impairment, together with selection criteria, exclusions, and provisos for the claimed compound families.
Claims Coverage
The document includes independent claims directed to defined Formula I and Formula II compound families and to selected compounds used in pharmaceutical and therapeutic methods. Across the claims, the core inventive features center on the permitted sigma-2 receptor antagonist compound framework, the selection of representative compound embodiments, and the use of the resulting compounds to inhibit amyloid beta effects on neuronal cells and treat Alzheimer’s disease.
Formula I compound framework with substituent and ring constraints
A compound of Formula I, or a pharmaceutically acceptable salt thereof, defined by independent selections for R1 through R11, including permitted substituent classes, optional linking to form specified ring systems or an O-C1-2 methylene-O group, provisos that R7, R8, R9, R10, and R11 are not all H, and exclusions of specified compounds.
Formula II compound framework with substituent scope and exclusions
A compound of Formula II defined by substituent scope for R3 through R6 and R8 through R10, including halogens, hydroxy, alkoxy, sulfonyl/sulfonamide motifs, and carbonyl-related groups, with optional ring linking, an O-C1-2 methylene-O bridge, and provisos excluding specified compounds.
Selected compounds for pharmaceutical composition
A compound or a pharmaceutically acceptable salt thereof, selected from a recited group, with dependent coverage including a pharmaceutical composition comprising the compound or salt together with a pharmaceutically acceptable carrier or excipient.
Selected compounds for inhibiting amyloid beta effects and treating Alzheimer’s disease
A compound or a pharmaceutically acceptable salt thereof, selected from a recited group, with dependent coverage including a method of inhibiting the effect of amyloid beta on a neuronal cell by administering an effective amount, and a method for treating Alzheimer’s disease by administering an effective amount to a subject with the disease.
Overall claim coverage centers on structurally defined sigma-2 receptor antagonist compound families and on pharmaceutical and therapeutic use claims. The inventive features are the compound definitions with extensive substituent and linking constraints, together with methods for inhibiting amyloid beta effects on neuronal cells and treating Alzheimer’s disease.
Stated Advantages
Inhibits amyloid beta effects on neuronal cells and synapses.
Prevents non-lethal amyloid beta pathology associated with membrane trafficking defects, exocytosis or membrane trafficking deficits, and synaptic dysfunction decline.
Provides competitive sigma-2 binding selectivity in assay evidence.
Improved bioavailability is stated for tested compounds.
Inhibits amyloid beta oligomer binding.
Inhibits membrane trafficking deficits.
Inhibits soluble amyloid beta oligomer-mediated cognitive effects.
Eliminates Aβ brain-derived trafficking deficits.
Counteracts non-lethal Aβ pathology, including synaptic dysfunction and synapse loss.
Addresses defects in long-term potentiation, including suppression of hippocampal LTP.
Includes a reported therapeutic phenotype criterion based on in vitro toxicity and hERG thresholds.
Documented Applications
Pharmaceutical compositions comprising the claimed compounds together with a pharmaceutically acceptable carrier or excipient.
Methods for inhibiting amyloid beta (Aβ) effects on neuronal cells by administering an effective amount of a compound or pharmaceutically acceptable salt thereof.
Methods for inhibiting Aβ-associated synapse loss or dysfunction and membrane trafficking change in neuronal cells.
Methods for treating Alzheimer’s disease, including cognitive decline, cognitive impairment, and mild cognitive impairment, by administering an effective amount of the compound or salt to a subject with the disease.
Associated method variants relating amyloid beta effects to cognitive decline in a subject showing or at risk of showing cognitive decline.
Associated method variants relating amyloid beta effects to cognitive impairment in Alzheimer’s disease.
In vitro membrane trafficking assay evaluation of sigma-2 receptor antagonist isoindoline or related compounds against Aβ1-42 oligomer effects, including synthetic and patient-derived Aβ oligomers.
In vivo evaluation in a transgenic AD fear-conditioning model.
Assessment of Aβ oligomer binding and synapse loss assays.
Autoradiography-based sigma receptor assessment.
Classification of sigma-2 agonist or antagonist behavior using MTS and caspase-3 assays.
Chemical preparation and support of compound synthesis for the evaluated isoindoline or related compounds, including gem-dimethyl amine and chiral intermediate preparation examples.
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