CFTR Modulators Correcting F508del Trafficking Defects
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation, are inadequate in effectively addressing the severe forms of the disease, as they fail to adequately correct the trafficking and functional defects in the CFTR protein, leading to persistent ion and fluid transport imbalances and associated complications.
Innovation Solution
Development of novel compounds, including those of Formula I, Formula Ia, Formula Ib, Formula Ic, and Formula Id, along with their tautomers, deuterated derivatives, and pharmaceutically acceptable salts, which act as CFTR modulators to correct trafficking and enhance channel function, potentially used in combination with existing CFTR potentiators and correctors like tezacaftor, lumacaftor, and ivacaftor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CFTR modulators are used to treat F508del mutation, then some correction of trafficking defect is achieved, but the correction is inadequate and severe disease forms persist
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of CFTR modulators through various substituents (R1, R2, R3, Ring A, Ring B, Ring C, W, X, Y, Q, Q′ parameters) to enhance the potency and efficacy of the compounds. This structural optimization aims to achieve more complete correction of CFTR trafficking and function, thereby treating severe disease forms that current modulators cannot adequately address.
2Productivity
If novel compounds are developed to enhance CFTR function, then anion and fluid transport is improved, but the complexity of treatment increases
Solution Approach 1:
The patent employs segmentation by dividing the treatment approach into distinct compound classes (Formula I, Ia, Ib, Ic, Id) with specific structural features that target different aspects of CFTR dysfunction. Each formula represents a segmented approach to correcting specific defects in CFTR processing, trafficking, or function, allowing for tailored treatment of different disease severities.
3Reliability
If combination therapy with multiple CFTR modulators is used, then CFTR function is more effectively corrected, but the manufacturing and dosing complexity increases
Solution Approach 1:
The patent applies merging by combining multiple CFTR modulating activities into single compounds or coordinated compound regimens. The disclosed compounds are designed to simultaneously address multiple defects in CFTR processing and function, potentially reducing the need for multiple separate medications and simplifying the treatment regimen while maintaining effective CFTR correction.
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 treating CFTR mediated diseases, including cystic fibrosis using such modulators and pharmaceutical compositions, combination therapies and combination pharmaceuticals employing those modulators, and processes and intermediates for making such modulators.