RyR Stabilizing Compounds for Neurodegenerative Disease
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Solution Overview
Problem
Current treatments for neurodegenerative diseases like Alzheimer's disease are ineffective due to late intervention and targeting of single diagnostic endpoints, such as amyloid aggregation, which do not improve synaptic damage, and existing RyR stabilizers like dantrolene may have pathogenic effects.
Innovation Solution
Development of novel RyR-targeted small molecule compounds that stabilize ryanodine receptor channels, normalizing aberrant ER calcium signaling and preserving synaptic functions, thereby reducing amyloid pathology and improving memory performance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dantrolene is used to stabilize RyR channels, then calcium signaling is normalized, but pathogenic effects occur including increased amyloid pathology
Solution Approach 1:
The patent modifies the chemical structure of dantrolene by changing specific parameters including replacing the nitrophenyl group with different aryl or heteroaryl groups, modifying the imidazolidine-2,4-dione core structure, and adjusting substituent positions and types. These parameter changes in the molecular structure aim to maintain calcium signaling normalization while eliminating the pathogenic effects associated with dantrolene's original structure
Solution Approach 2:
The patent applies local quality by making specific modifications to particular regions of the dantrolene molecule while preserving other critical regions. The modifications are localized to specific functional groups (such as the aryl substituent at position 1 and the heterocyclic ring system) to achieve selective improvement of therapeutic properties while maintaining the essential calcium channel stabilizing activity
2Quantity of substance
If amyloid levels are reduced through APP processing targeting, then amyloid aggregation decreases, but synaptic damage is not improved and cognitive function does not enhance
Solution Approach 1:
Instead of targeting amyloid aggregation as the primary therapeutic approach, the patent inverts the strategy by targeting the downstream consequence of amyloid pathology - aberrant calcium signaling through RyR channel dysfunction. This inverted approach addresses the actual mechanism causing synaptic damage and cognitive decline rather than merely reducing amyloid levels
Solution Approach 2:
The patent introduces calcium signaling normalization as an intermediary mechanism between amyloid pathology and synaptic dysfunction. By stabilizing RyR channels and normalizing calcium release, the compounds act as mediators that connect the reduction of pathogenic effects to improved synaptic function and cognitive outcomes, bridging the gap that direct amyloid-targeting therapies fail to cross
Data Source
AI summary
Disclosed herein are methods and compositions comprising compounds capable of normalizing neuronal calcium dyshomeostasis. Also disclosed are methods comprising these compounds for treating neuronal or neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, fronto-temporal dementia, Pick's disease, chronic traumatic encepholopathy, traumatic brain injury, stroke, cerebellar ataxia, multiple sclerosis, Down syndrome, and aging-related CNS disorders.