Formula I Compounds for CFTR Protein Stabilization
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Solution Overview
Problem
There is a need for compounds and methods to increase cystic fibrosis transmembrane conductance regulator (CFTR) activity and treat CFTR-related diseases, particularly those associated with protein misfolding, such as cystic fibrosis caused by the ΔF508 mutation, which disrupts protein folding and trafficking, leading to respiratory and organ dysfunction.
Innovation Solution
The use of specific compounds, represented by formulas Ia, Ib, Ic, Id, II, and III, or their pharmaceutically acceptable salts, in combination with CFTR amplifier, corrector, and potentiator compounds, administered to patients with CFTR-related diseases to enhance CFTR activity, correct protein misfolding, and improve protein trafficking.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If compounds are used to increase CFTR activity and stabilize CFTR protein, then CFTR function and protein stability are improved, but the complexity of treatment regimens increases due to combination therapy requirements
Solution Approach 1:
The patent combines multiple CFTR modulators (correctors and potentiators) with compounds of Formula I into a single combination therapy regimen. This merging of multiple therapeutic agents addresses the technical contradiction by achieving synergistic effects that improve CFTR function and protein stability while managing the complexity through a defined combination protocol rather than separate treatments.
Solution Approach 2:
The treatment approach uses composite therapeutic compositions comprising multiple distinct compounds (Formula I compounds, CFTR correctors, and CFTR potentiators). This composite strategy leverages the complementary mechanisms of each compound class to achieve reliable CFTR function restoration, where each component contributes a specific therapeutic effect that enhances overall treatment efficacy.
2Reliability
If combination therapy with multiple CFTR modulators is administered, then CFTR activity and protein stability are enhanced, but the manufacturing and administration complexity increases
Solution Approach 1:
The patent segments the combination therapy into distinct compound classes (Formula I compounds, CFTR correctors, and CFTR potentiators) with defined roles and mechanisms. This segmentation allows for standardized manufacturing of individual components that can be combined in controlled formulations, reducing overall manufacturing complexity compared to developing entirely new combination products.
Solution Approach 2:
The compounds of Formula I exhibit multi-functionality by acting as CFTR modulators that can be combined with various corrector and potentiator compounds. This universal applicability across different CFTR mutation types and combination partners simplifies manufacturing strategies, as the core Formula I compound can be produced using the same process regardless of which specific corrector or potentiator is paired with it.
Data Source
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AI summary
The present disclosure features methods of treating a condition associated with decreased CFTR activity or a condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of compounds disclosed herein.