CFTR Modulating Compounds for Protein Trafficking and Channel Gating
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Solution Overview
Problem
Current treatments for cystic fibrosis (CF) and other CFTR-mediated disorders are inadequate, particularly for severe forms, due to mutations in the CFTR protein leading to reduced anion transport and defective channel gating, resulting in mucus accumulation, respiratory issues, pancreatic insufficiency, and infertility, with no cure available.
Innovation Solution
Development of CFTR modulating compounds, including (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexan-5-yl}-9-oxa-2λ6-thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (Compound I) and its deuterated derivatives, along with pharmaceutical compositions containing these compounds, which act as CFTR correctors and potentiators to enhance ion transport and correct protein trafficking.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CFTR modulating compounds are developed to correct protein trafficking and enhance ion transport, then anion transport is improved, but the complexity of treatment options increases
Solution Approach 1:
The patent modifies the CFTR protein through chemical modulation, changing its functional parameters (trafficking efficiency, channel gating, ion conductance) to restore normal anion transport function despite the presence of disease-causing mutations
Solution Approach 2:
The modulating compounds act as intermediary substances that bind to CFTR proteins and mediate the correction of defective trafficking and gating, enabling the mutated protein to function appropriately
2Ease of operation
If existing CFTR treatments are used, then some symptom management is achieved, but the severity of CF disease remains untreated
Solution Approach 1:
The modulating compounds perform preliminary corrective actions on the CFTR protein before it can cause disease pathology, addressing the root cause (defective trafficking and gating) rather than merely managing symptoms
Solution Approach 2:
The patent converts the harmful effect of CFTR mutations into a beneficial outcome by using the mutated protein's residual functionality and directing it toward appropriate trafficking and gating correction, thereby reducing disease severity
Data Source
AI summary
Compound (I), deuterated derivatives, and pharmaceutically acceptable salts of any of the foregoing are disclosed. Methods of treating cystic fibrosis using these compounds are also disclosed.