GCase Modulators Enhancing Brain Penetration for Neurodegenerative Disease Treatment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for Parkinson's disease and Gaucher's disease, particularly enzyme replacement therapy, do not effectively address neurological manifestations due to limited brain penetration, and existing small-molecule modulators of β-glucocerebrosidase (GCase) lack sufficient brain permeability and efficacy in reducing alpha-synuclein accumulation and related neurodegenerative effects.
Innovation Solution
Development of compounds and their pharmaceutically acceptable salts that modulate β-glucocerebrosidase (GCase) activity, including prodrugs, to enhance permeability and increase enzyme levels and activity in the brain, thereby treating neurodegenerative diseases like Parkinson's and lysosomal storage disorders such as Gaucher's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy (recombinant human GCase) is administered, then visceral and haematological complications of Gaucher's disease are controlled, but neurological manifestations are not improved due to lack of brain penetration
Solution Approach 1:
The patent employs permeability enhancement compounds as intermediary agents that facilitate the transport of GCase or GCase activators across the blood-brain barrier. These compounds act as mediators between the administered therapy and the neural tissue, enabling brain penetration without directly treating the neurological symptoms themselves.
Solution Approach 2:
The invention modifies the physical and chemical parameters of the administered compounds to enhance their permeability properties. By changing parameters such as molecular size, charge distribution, and lipophilicity, the therapy achieves effective brain penetration while maintaining its ability to control visceral and haematological complications.
2Reliability
If small-molecule GCase modulators are used, then alpha-synuclein levels and behavioural deficits are reduced in rodent models, but brain permeability and efficacy are insufficient
Solution Approach 1:
The patent introduces permeability enhancement compounds as intermediary agents that facilitate the transport of GCase or GCase activators across the blood-brain barrier. These compounds act as mediators between the administered therapy and the neural tissue, enabling brain penetration without directly treating the neurological symptoms themselves.
Solution Approach 2:
The invention combines multiple functional components into composite therapeutic formulations. These composite materials integrate GCase modulators with permeability enhancement agents, creating a synergistic effect that simultaneously achieves brain penetration and alpha-synuclein reduction, thereby addressing both the efficacy and permeability deficiencies.
3Reliability
If recombinant human GCase is administered via enzyme replacement therapy, then glucosylceramide accumulation is reduced in lysosomes, but the enzyme does not penetrate the brain
Solution Approach 1:
The patent employs permeability enhancement compounds as intermediary agents that facilitate the transport of GCase or GCase activators across the blood-brain barrier. These compounds act as mediators between the administered therapy and the neural tissue, enabling brain penetration without directly treating the neurological symptoms themselves.
Solution Approach 2:
The invention replaces the mechanical limitation of protein-based enzyme therapy with small-molecule based permeability enhancement agents. This substitution allows the therapy to overcome the blood-brain barrier through molecular diffusion and transport mechanisms rather than relying on the protein's natural penetration capability.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively modulate GCase activity, increasing enzyme levels and activity in the brain, which helps in reducing alpha-synuclein accumulation and improving neurological symptoms in Parkinson's disease and Gaucher's disease, providing a more comprehensive treatment approach than existing therapies.
Implementation Method 1
compounds which modulate glycosidases... compounds for modulating a β-glucocerebrosidase (GCase)... increasing enzyme levels and activity in the brain
Implementation Method 2
enhance permeability and increase enzyme levels and activity in the brain... providing a more comprehensive treatment approach
Data Source
AI summary
The invention provides compounds for modulating glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds.