Arylamide CFTR Modulators for ΔF508 Folding and Trafficking
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Solution Overview
Problem
There is no cure for cystic fibrosis, and existing CFTR modulators do not adequately address the functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to severe physiological consequences such as reduced lung function, chronic infection, and dysfunction of additional organs like the pancreas and intestine.
Innovation Solution
Development of arylamide compounds that modulate CFTR function, potentially enhancing channel activity and correcting the deficiencies caused by mutations like ΔF508, thereby treating conditions associated with deficient CFTR activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule CFTR modulators are used to increase CFTR channel function, then CFTR activity is improved, but the disease remains fatal and no cure exists
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of CFTR modulator compounds through systematic variation of molecular parameters (substituents R1-R10, ring structures, and functional groups) to optimize CFTR channel function and therapeutic effectiveness, transforming existing modulators into more effective treatments
2Reliability
If the ΔF508 mutation causes misfolded CFTR protein retention in the endoplasmic reticulum, then CFTR cannot reach the plasma membrane, but the misfolded protein is degraded by the ubiquitin-proteasome system
Solution Approach 1:
The patent uses CFTR modulator compounds as intermediaries that bind to misfolded CFTR protein and facilitate its proper folding and trafficking to the plasma membrane, preventing degradation by the ubiquitin-proteasome system and enabling functional CFTR channels to reach their destination
3Adaptability or versatility
If CFTR dysfunction impacts multiple downstream pathways in organs such as pancreas, intestine, and gall bladder, then multiple physiological pathways require correction, but current treatments lack comprehensive therapy
Solution Approach 1:
The patent develops CFTR modulator compounds with universal applicability across multiple CFTR-mediated diseases and organ systems, creating a single therapeutic agent that can address diverse downstream pathological effects in the lungs, pancreas, intestine, and gall bladder through restoration of CFTR function
Data Source
AI summary
The present disclosure relates to substituted aryl amide compounds, according to Formula (I):pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.