CFTR Modulators Formula I Compounds
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Solution Overview
Problem
There is a need for modulators of CFTR activity to treat CFTR-mediated diseases, including cystic fibrosis and other conditions characterized by defective protein trafficking and ion transport imbalances, as existing treatments are limited in efficacy and scope.
Innovation Solution
Development of compounds with the general formula (I) or their pharmaceutically acceptable salts, which modulate CFTR activity by increasing or decreasing its function, thereby treating a range of diseases associated with defective ion and fluid transport, such as cystic fibrosis, hereditary emphysema, and neurodegenerative disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CFTR treatments are used, then some therapeutic effect is achieved, but efficacy is limited and scope is restricted
Solution Approach 1:
The patent describes a series of compounds with general formula (I) that can modulate CFTR activity across multiple disease contexts. The compounds are designed to work on CFTR-mediated diseases including cystic fibrosis and other conditions characterized by defective protein trafficking and ion transport imbalances, providing universal therapeutic coverage beyond existing single-indication treatments
Solution Approach 2:
The patent employs structural modification of the core compound framework by varying substituents R1, R'1, R2, R3, R'3, R4 and parameter n to create a series of analogs with optimized CFTR modulatory activity. This systematic parameter change approach enables fine-tuning of therapeutic efficacy and broadening of treatment scope across different disease manifestations
2Productivity
If CFTR activity is modulated to treat disease, then ion and fluid transport improves, but underlying defects in protein trafficking may persist
Solution Approach 1:
The compounds of formula (I) act as pharmacological intermediaries that bind to CFTR and modulate its activity. These small molecule mediators can enhance the function of misfolded CFTR proteins (such as ΔF508 mutants) that are retained in the endoplasmic reticulum, allowing them to fold correctly and traffic to the cell membrane, thereby addressing both the transport defect and the underlying protein trafficking issue
Solution Approach 2:
The patent describes compounds that can be administered before complete disease manifestation or in combination with other therapies. By preliminarily correcting CFTR protein folding and trafficking, these compounds prevent the accumulation of severe ion transport defects and associated pathological changes in mucus, sweat glands, and respiratory epithelium
Data Source
AI summary
Compounds of the present invention, and pharmaceutically acceptable composition thereof, are useful as modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ("CFTR"). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention.