CFTR Modulators for Cystic Fibrosis Trafficking Correction
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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.
Innovation Solution
Development of novel compounds, including those represented by Formula I, which act as CFTR correctors to facilitate proper trafficking and function of the CFTR protein, potentially in combination with existing modulators like tezacaftor, ivacaftor, and lumacaftor, to enhance ion transport across epithelial membranes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments targeting F508del mutation are used, then some CFTR function is restored, but trafficking and functional defects are not adequately corrected
Solution Approach 1:
The treatment approach is segmented into multiple components: a first CFTR modulator (corrector) that specifically addresses trafficking defects to deliver CFTR to the cell membrane, and a second CFTR modulator (potentiator) that enhances the functional activity of the delivered channels. This segmentation allows each component to optimize for its specific function, thereby resolving the contradiction between reliable trafficking correction and productive ion transport.
Solution Approach 2:
The patent combines multiple CFTR modulators with different mechanisms of action into a single therapeutic regimen. By merging the trafficking correction function of correctors with the functional enhancement function of potentiators, the treatment achieves both reliable CFTR delivery to the membrane and high productivity in ion transport, eliminating the trade-off between these two parameters.
2Quantity of substance
If CFTR channel number in membrane is increased, then anion transport improves, but defective gating persists
Solution Approach 1:
The therapeutic strategy segments the problem into two distinct functional requirements: increasing the quantity of CFTR channels in the membrane (addressed by correctors) and improving the gating reliability of each channel (addressed by potentiators). By applying separate modulators for each function, the patent achieves both high channel quantity and reliable gating without compromise.
Solution Approach 2:
The patent changes multiple parameters of CFTR function simultaneously: it increases the number of functional channels in the membrane (quantity parameter) while also modifying the gating kinetics and open probability (reliability parameter) through the action of different modulators. This multi-parameter optimization resolves the contradiction between channel quantity and gating reliability.
3Manufacturing precision
If CFTR protein folding is corrected, then trafficking to plasma membrane improves, but channel function remains defective
Solution Approach 1:
The patent segments the CFTR correction process into two distinct stages: first, correcting the protein folding and trafficking (manufacturing precision) using correctors; second, enhancing the channel function (productivity) using potentiators. This segmentation allows optimization of each stage independently, achieving both proper folding and high functional output.
Solution Approach 2:
The correctors perform a preliminary action by ensuring proper CFTR folding and delivery to the plasma membrane before the potentiators act to enhance channel function. This preliminary correction of manufacturing precision creates the foundation for subsequent productivity enhancement, resolving the contradiction between proper folding and functional efficiency.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the structure: (I), 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.