Compositions for treating neurodegenerative diseases
Inventors
Rishton, Gilbert M. • Look, Gary C. • Catalano, Susan M.
Assignees
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Publication Number
US-11214540-B2
Publication Date
2022-01-04
Expiration Date
Abstract
The present disclosure relates to novel compounds, and pharmaceutical compositions thereof, useful for treating for treating neurodegenerative diseases, including Alzheimer's disease and cognitive decline. Methods for inhibiting synapse number decline or membrane trafficking abnormalities associated with exposure of a neuronal cell to Abeta species are also disclosed. Representative members of these compounds include:
Core Innovation
The disclosure describes neurodegenerative-disease therapeutics based on compounds of Formula I or Formula IIa and pharmaceutically acceptable salts thereof, with defined substituent sets for R_a through R_e or R_k and R_l, together with R1 and an optionally substituted cyclic amino group R2 or an R12 selection set. The compounds are presented as the basis for drug candidates targeting Alzheimer’s disease and neurodegenerative disease, including specific Formula IIa compound embodiments and example structures.
The therapeutic concept centers on sigma-2 receptor functional antagonism to inhibit neuronal synapse loss and soluble amyloid-beta oligomer binding associated with synaptic plasticity failure. The disclosure relates these pathological outcomes to Abeta species in neuronal cells, including abnormal membrane trafficking, synapse number loss, and cognitive decline, and states a therapeutic phenotype in which Abeta oligomer effects are inhibited.
The disclosure further includes pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier or diluent. Treatment and prophylaxis contexts are described for Alzheimer’s disease, inhibition of amyloid beta effects on neuronal cells, and inhibition of cognitive decline, with compounds also described as maintaining brain penetrability and plasma/metabolic stability.
Claims Coverage
The consolidated claim coverage includes one independent compound claim and related dependent and method claims. The inventive features focus on the Formula I or Formula IIa chemical scaffold with defined substituent selections, pharmaceutical compositions containing a therapeutically effective amount, and method-of-use embodiments directed to Alzheimer’s disease, amyloid beta effects on neuronal cells, synapse loss, and cognitive decline.
Formula I compound with defined substituent sets
A compound of Formula I or pharmaceutically acceptable salt thereof, wherein each of R_a, R_b, R_c, R_d and R_e is independently selected from H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino; R1 is selected from hydrogen, alkyl, phenyl, or —CH2C(CH3)2; and R2 is an optionally substituted cyclic amino group.
Selected from depicted group of chemical structures
A claimed compound is selected from a specified group of depicted chemical structures, or a pharmaceutically acceptable salt thereof.
Formula IIa scaffold with defined substituent sets
A compound of Formula IIa, wherein each of R_k and R_l is independently selected from H, hydroxyl, halo, alkyl, alkoxy, CF3, SO2CH3, and morpholino, and R12 is selected from an enumerated set including aryloxy, alkenyloxy, alkoxy, aminoalkyl, hydroxyalkyl, cyclic amines, and O(CH2)2OC(O)CH3.
Pharmaceutical composition with therapeutically effective amount and carrier or diluent
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Treating Alzheimer’s disease by administering the composition
Treating Alzheimer’s disease by administering to a subject a therapeutically effective amount of a pharmaceutical composition.
Inhibiting amyloid beta effect on a neuronal cell
Inhibiting the effect of amyloid beta on a neuronal cell by administering to a subject a therapeutically effective amount of a pharmaceutical composition.
Inhibiting cognitive decline in a subject who has or is at risk
Inhibiting cognitive decline by administering a therapeutically effective amount of a pharmaceutical composition to a subject who has or is at risk of developing cognitive decline.
Overall, the claim set centers on Formula I and Formula IIa compounds with defined substituent choices, pharmaceutical compositions containing those compounds, and method claims directed to Alzheimer’s disease, inhibition of amyloid beta effects on neuronal cells, and inhibition of cognitive decline.
Stated Advantages
Inhibits cognitive decline.
Inhibits the effect of amyloid beta on neuronal cells.
Treats Alzheimer’s disease.
Maintains brain penetrability.
Maintains plasma stability.
Maintains metabolic stability.
Prevents synapse loss.
Documented Applications
Therapeutic treatment of Alzheimer’s disease by administering a therapeutically effective amount of the defined pharmaceutical composition to a subject.
Inhibiting cognitive decline by administering a therapeutically effective amount of the defined pharmaceutical composition to a subject who has or is at risk of developing cognitive decline.
Inhibiting the effect of amyloid beta on a neuronal cell by administering the defined pharmaceutical composition to a subject.
Predicted behavioral efficacy in animal models for compounds that match in vitro assay criteria [procedural detail omitted for safety].
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