CFTR Modulator Compounds for F508del Folding and Channel Gating
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation in the CFTR protein, are inadequate in effectively addressing the reduced anion transport and defective channel gating, leading to severe respiratory and digestive issues, with no cure available.
Innovation Solution
Development of novel compounds, including those of Formulae I, II, III, and IV, and their derivatives, which modulate CFTR function to improve anion and fluid transport across epithelial cells, potentially complemented by CFTR potentiators and correctors like tezacaftor, ivacaftor, and lumacaftor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If F508del mutation is present in CFTR, then protein folding is impaired and trafficking to plasma membrane is blocked, but this leads to reduced anion transport and defective channel gating
Solution Approach 1:
The patent employs CFTR modulators as intermediary compounds that bind to the defective CFTR protein and facilitate its proper folding and trafficking. These small molecule mediators act as bridges between the mutated protein and the cellular quality control mechanisms, enabling the F508del-CFTR to escape ER retention and reach the plasma membrane where it can function.
Solution Approach 2:
The invention utilizes compounds that alter the biophysical parameters of CFTR protein folding and channel gating. By changing the conformational parameters and electrochemical gradients, these modulators restore anion transport function without requiring correction of the underlying genetic mutation.
2Reliability
If current CFTR treatments are used, then some anion transport is restored, but respiratory and digestive issues remain severe with no cure available
Solution Approach 1:
The patent employs dynamic combination therapy regimens where CFTR modulators are administered in specific sequences and combinations to address multiple aspects of CFTR dysfunction simultaneously. This dynamic approach allows for coordinated correction of folding defects, trafficking issues, and channel gating problems, providing comprehensive treatment beyond static monotherapy.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies employing those modulators, and processes and intermediates for making such modulators.