CFTR Modulators Correcting F508del Folding and Gating
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for cystic fibrosis (CF) do not effectively address the underlying ion and fluid transport imbalances caused by mutations in the CFTR gene, particularly the F508del mutation, leading to severe respiratory and digestive issues.
Innovation Solution
Development of novel compounds, including those of Formulae (1), (2), and (3), and their pharmaceutically acceptable salts and deuterated derivatives, which act as modulators of the CFTR protein, correcting trafficking defects and enhancing channel function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for cystic fibrosis, then patients receive standard care, but the underlying ion and fluid transport imbalances caused by CFTR mutations are not effectively addressed
Solution Approach 1:
The patent employs CFTR modulators as intermediary compounds that mediate between the defective CFTR protein and normal physiological function. These small molecule drugs act as pharmacological chaperones or gating modulators to restore ion transport without directly correcting the genetic mutation, thereby addressing the harmful transport imbalances while maintaining treatment feasibility
Solution Approach 2:
The invention utilizes compounds that change the functional parameters of the CFTR protein, including its stability, trafficking efficiency, and channel gating properties. By modifying these protein parameters through pharmacological intervention, the treatment restores adequate ion and fluid transport across epithelial surfaces
2Adaptability or versatility
If the F508del mutation is present, then CFTR protein folding is prevented, but the mutation occurs in approximately 70% of cystic fibrosis cases
Solution Approach 1:
The patent addresses the F508del mutation by segmenting the problem into distinct phases: preventing degradation in the endoplasmic reticulum, facilitating trafficking to the plasma membrane, and ensuring proper channel gating. CFTR corrector compounds specifically target the folding and trafficking phase, while potentiator compounds address the gating phase, allowing tailored intervention for this prevalent mutation
Solution Approach 2:
Pharmacological chaperone compounds act as molecular intermediaries that bind to the defective CFTR protein and stabilize its folded conformation, enabling it to escape degradation and traffic to the cell surface. These intermediary molecules bridge the gap between the mutated protein structure and functional requirement
3Quantity of substance
If the number of CFTR channels in the membrane is reduced, then anion transport decreases, but this leads to enhanced mucus accumulation and microbial infections
Solution Approach 1:
The patent employs preliminary pharmacological action to prevent the degradation of CFTR channels before they reach the plasma membrane. CFTR corrector compounds administered early in the disease course or prophylactically increase channel abundance at the cell surface, thereby preventing the downstream harmful effects of mucus accumulation and infections before they occur
Solution Approach 2:
The treatment creates a positive feedback loop where increased CFTR channel function improves ion transport, which in turn enhances mucus clearance and reduces infection risk. This restored physiological function further supports CFTR expression and activity, creating a beneficial cycle that counteracts the disease progression
4Reliability
If CFTR channel gating is defective, then anion and fluid transport are reduced, but the channels remain less functional than wild-type CFTR
Solution Approach 1:
The patent utilizes CFTR potentiator compounds that specifically change the gating parameters of CFTR channels already present at the plasma membrane. These compounds increase the probability of channel opening and duration of open states, thereby enhancing anion and fluid transport without requiring changes in channel number or folding
Solution Approach 2:
The invention employs dynamic modulation of CFTR channel gating through small molecule compounds that bind to and alter the conformational equilibrium of the channel. This dynamic intervention increases the frequency and duration of channel opening events, restoring adequate ion and fluid transport despite the underlying genetic defect
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 cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.