Formula I Compounds Modulating ABC Transporter Activity
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Solution Overview
Problem
Current treatments for ABC transporter-mediated diseases, such as Cystic Fibrosis, lack effective modulators to address defective protein trafficking and activity, leading to impaired ion and fluid transport, and there is a need for compounds that can modulate ABC transporter activity to treat various diseases associated with defective protein folding and secretion.
Innovation Solution
Development of compounds with a specific formula that act as modulators of ABC transporter activity, including CFTR, to regulate anion secretion and trafficking, thereby addressing the underlying defects in protein processing and secretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for ABC transporter-mediated diseases are used, then disease management is maintained with existing therapies, but effective modulators to address defective protein trafficking and activity are lacking
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of compounds to alter their interaction with ABC transporters. The general formula I compounds incorporate specific substituents (R1-R6, G1-G3, Ar1) that can be varied to change binding affinity, selectivity, and functional outcomes, enabling effective modulation of defective protein trafficking and transporter activity.
Solution Approach 2:
The patent introduces intermediary compounds (formula I) that act as modulators between therapeutic agents and ABC transporters. These compounds serve as mediators that can enhance or inhibit transporter function, address defective protein trafficking, and improve the effectiveness of disease treatments without directly correcting the underlying genetic defect.
2Reliability
If ABC transporter activity is not modulated, then protein folding and secretion defects persist, but treating these defects requires effective modulators that are currently unavailable
Solution Approach 1:
The patent applies segmentation by dividing the complex problem of ABC transporter modulation into specific structural components. The general formula I is segmented into distinct functional elements (G1-G3 groups, Ar1 aromatic systems, substituent patterns) that can be independently optimized to achieve desired effects on protein folding, secretion, and transporter activity.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying structural parameters (substituents R1-R6, linkers G1-G3, aromatic systems Ar1) to optimize compound properties for addressing protein folding and secretion defects. This structured approach to parameter variation enables the development of effective therapeutic modulators.
3Productivity
If defective protein trafficking is not addressed, then ion and fluid transport remains impaired, but treating this requires modulators that can regulate ABC transporter activity
Solution Approach 1:
The patent implements feedback mechanisms through modulators that can sense and respond to ABC transporter dysfunction. The formula I compounds provide feedback by binding to transporters and inducing conformational changes or functional modulation that restores proper ion and fluid transport efficiency.
Solution Approach 2:
The patent applies parameter changes by modifying transporter function through compound binding, which alters kinetic parameters, binding affinities, and transport rates. This enables restoration of impaired ion and fluid transport without requiring complete correction of the underlying protein trafficking defect.
Data Source
AI summary
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.