CFTR Modulators Correcting Trafficking and Gating
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly severe forms, lack effective compounds that can address the defective trafficking and channel gating issues caused by mutations like F508del in the CFTR protein, leading to impaired anion and fluid transport across epithelia.
Innovation Solution
Development of novel compounds, including those represented by Formula I, IIa, IIb, III, IV, V, and VI, along with their tautomers, deuterated derivatives, and pharmaceutically acceptable salts, which act as CFTR modulators to correct trafficking and enhance channel function, potentially used in combination with existing CFTR modulators like tezacaftor and ivacaftor.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for cystic fibrosis, then current standard of care is maintained, but effective treatment for severe forms with defective trafficking and channel gating is lacking
Solution Approach 1:
The patent employs parameter changes by developing compounds with specific molecular structures (Formulas I-VI) that target different aspects of CFTR function. The compounds are designed to modify parameters such as trafficking efficiency and channel gating properties, thereby treating severe forms of cystic fibrosis that respond poorly to conventional therapies.
2Reliability
If CFTR modulators are developed to correct trafficking, then channel function is enhanced, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the CFTR modulation function into distinct compound classes (Formulas I-VI), each targeting specific aspects of CFTR pathology. This segmentation allows for specialized compounds that address trafficking defects, channel gating issues, or both, thereby managing complexity through functional categorization.
Solution Approach 2:
The patent employs universality by designing a series of compounds (Formulas I-VI) that can address multiple aspects of CFTR dysfunction within a unified therapeutic approach. These compounds may simultaneously improve trafficking and enhance channel function, reducing the need for multiple separate treatments.
3Reliability
If combination therapies with existing CFTR modulators are used, then therapeutic efficacy is improved, but treatment complexity increases
Solution Approach 1:
The patent applies merging by combining the new compounds (Formulas I-VI) with existing CFTR modulators like tezacaftor and ivacaftor in combination therapies. This merging leverages the complementary mechanisms of action to achieve synergistic effects, improving therapeutic efficacy for patients with various CFTR mutations.
Data Source
AI summary
This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) having the core structure: 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, and processes and intermediates for making such modulators.