CFTR Modulator Combinations for F508del Trafficking and Gating Defects
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Solution Overview
Problem
Current treatments for cystic fibrosis and other CFTR-mediated diseases, particularly severe forms, are inadequate, as they fail to effectively address the reduced anion and fluid transport issues caused by CFTR mutations like F508del, leading to mucus accumulation and associated health complications.
Innovation Solution
Development of novel compounds, including those of Formula I and its derivatives, which modulate CFTR function to improve anion and fluid transport, potentially combined with CFTR modulating agents like potentiators and correctors, to enhance channel activity and correct trafficking defects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CFTR modulators are used to treat F508del mutation, then some improvement in CFTR function is achieved, but the treatment is inadequate for severe forms of the disease due to failure to adequately correct trafficking and functional defects
Solution Approach 1:
The patent combines multiple CFTR modulators with different mechanisms of action (correctors and potentiators) into a single therapeutic regimen. This merging approach addresses both trafficking defects and functional defects simultaneously, providing more comprehensive correction of CFTR abnormalities than single agents alone.
Solution Approach 2:
The invention uses composite therapeutic strategies that combine compounds with complementary pharmacological properties. By integrating multiple modulators that target different aspects of CFTR pathology (folding, trafficking, gating), the treatment achieves synergistic effects that overcome the limitations of individual agents.
2Productivity
If CFTR modulators are developed to enhance protein activity, then anion and fluid transport is improved, but the complexity of achieving adequate correction of multiple defects increases
Solution Approach 1:
The patent divides the complex task of correcting CFTR defects into distinct functional components: correctors that address trafficking defects and potentiators that enhance channel function. This segmentation allows each component to be optimized for its specific target, making the overall complex problem more manageable through modular approaches.
Solution Approach 2:
The invention introduces intermediary compounds that facilitate CFTR maturation and trafficking as intermediate steps before the channel reaches its functional state. These intermediary agents bridge the gap between defective nascent protein and fully functional membrane channel, enabling progressive correction of multiple defects.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure: pharmaceutical compositions containing at least one such modulator, methods of treatment of cystic fibrosis using such modulators and pharmaceutical compositions, combination therapies, and processes and intermediates for making such modulators.