CFTR Modulator Compounds for Cystic Fibrosis Treatment
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Solution Overview
Problem
Current treatments for cystic fibrosis, caused by mutations in the CFTR gene, particularly the ΔF508 mutation, fail to effectively modulate CFTR activity, leading to impaired chloride transport and severe respiratory and digestive issues, with existing therapies not adequately addressing the defective protein folding and trafficking.
Innovation Solution
Development of specific compounds, such as those represented by Formula I, which are used in pharmaceutical compositions to modulate CFTR activity, including structures like or their pharmaceutically acceptable salts, to enhance CFTR function in the cell membrane, potentially combined with other agents like mucolytics, bronchodilators, or antibiotics, for treating cystic fibrosis and other related conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule potentiators are used to increase CFTR channel opening probability, then chloride transport is improved, but the therapy does not adequately address defective protein folding and trafficking
Solution Approach 1:
The patent applies universality by developing CFTR modulators that can address multiple types of CFTR defects (folding, trafficking, and channel gating) through a single therapeutic agent or combination regimen. The compounds of Formula I are designed to have broad applicability across different CFTR mutation types, particularly targeting both folding defects and channel gating issues, thereby providing a versatile treatment approach that overcomes the limitation of existing potentiators which only address channel opening probability.
2Object-affected harmful factors
If existing therapies are used to treat CF, then some symptom relief is achieved, but the underlying defects in protein folding and trafficking are not adequately addressed
Solution Approach 1:
The patent applies preliminary action by developing compounds that act upstream in the CFTR defect pathway, addressing protein folding and trafficking defects before the CFTR protein reaches the cell membrane. By targeting the early stages of CFTR biogenesis and stabilization, the compounds prevent the formation of defective channels, thereby addressing the root cause rather than merely mitigating downstream symptoms like impaired chloride transport.
3Reliability
If compounds are designed to increase functional CFTR channels in the membrane, then chloride transport is improved, but the complexity of the pharmaceutical composition increases
Solution Approach 1:
The patent applies segmentation by dividing the CFTR modulator functionality into distinct molecular components represented by the variable groups in Formula I (R1, R2, R3, R4, R5, R6, m, n). This modular structure allows for systematic optimization of different functional aspects (solubility, potency, selectivity) through independent variation of substituent groups, thereby managing molecular complexity while achieving multiple therapeutic objectives simultaneously.
Data Source
AI summary
This invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R is COOH or CH2OH.