Sulfonyl Cyclic Derivatives for Low-Concentration TRPML1 Activation
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Solution Overview
Problem
Current TRPML activators, such as ML-SA1, require high concentrations for effective activation and are metabolically labile, leading to poor oral bioavailability and systemic exposure, limiting their therapeutic potential for lysosome storage diseases, neurodegenerative diseases, oxidative stress-related diseases, metabolic diseases, and ageing.
Innovation Solution
Development of novel sulfonyl cyclic derivatives that act as potent TRPML1 agonists, offering improved solubility and oral bioavailability, capable of modulating TRPML activities to treat associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current TRPML activators (e.g., ML-SA1) are used, then TRPML channels can be activated, but high concentrations are required and metabolic lability leads to poor oral bioavailability and systemic exposure
Solution Approach 1:
The patent modifies the chemical structure of TRPML activators by introducing specific molecular features (e.g., rigid bicyclic frameworks, strategic functional group placement) that enhance binding affinity and metabolic stability. These structural parameter changes enable effective TRPML activation at lower concentrations while improving oral bioavailability through reduced metabolic lability.
2Reliability
If current TRPML activators are used, then TRPML channels can be activated, but metabolic lability leads to poor oral bioavailability and systemic exposure
Solution Approach 1:
The patent introduces metabolic stabilization through specific chemical modifications including the use of metabolically stable functional groups, strategic placement of electron-withdrawing groups to reduce enzymatic susceptibility, and incorporation of rigid structural elements that protect against metabolic degradation. These changes maintain TRPML activation efficacy while significantly improving metabolic stability and oral bioavailability.
3Quantity of substance
If novel sulfonyl cyclic derivatives are developed, then solubility and oral bioavailability are improved, but compound complexity increases
Solution Approach 1:
The patent achieves improved solubility and oral bioavailability through controlled structural modifications including the introduction of polar sulfonyl groups, cyclic frameworks that enhance crystal packing efficiency, and strategic substitution patterns. These changes are designed to balance solubility enhancement with maintaining reasonable structural complexity for synthetic feasibility.
Data Source
AI summary
The invention provides novel sulfonyl cyclic derivatives, and compositions and methods of preparation and use thereof, that are useful in treating various diseases and disorders related to TRPML activities such as lysosome storage diseases, muscular dystrophy, neurodegenerative diseases, oxidative stress or reactive oxygen species (ROS) related diseases, metabolic diseases, metastatic cancer, and ageing.