CFTR Modulators Restore Ion Transport to Reduce Mucus
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Solution Overview
Problem
Current treatments for cystic fibrosis and related conditions lack effective modulators for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which are crucial for managing ion and fluid transport disruptions in epithelial cells, leading to mucus accumulation and infections.
Innovation Solution
Development of novel substituted pyridine compounds, such as 1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide, and their pharmaceutically acceptable salts, which act as CFTR modulators to restore chloride and bicarbonate permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for cystic fibrosis are used, then patient survival is maintained, but ion and fluid transport disruptions in epithelial cells remain unaddressed, leading to mucus accumulation and infections
Solution Approach 1:
The patent applies parameter changes by developing novel chemical compounds with specific molecular structures (Formula I compounds) that modify the functional parameters of CFTR protein. These compounds change the gating behavior and conductance properties of the mutant CFTR channel, restoring its ability to transport chloride and bicarbonate ions, thereby addressing the ion and fluid transport disruptions that lead to mucus accumulation and infections
Solution Approach 2:
The patent uses small molecule compounds as intermediaries that bind to and modulate the CFTR protein. These intermediary molecules act as bridges between the therapeutic goal (restoring ion transport) and the target (mutant CFTR protein), facilitating the correction of CFTR function without requiring gene therapy or other complex interventions
2Reliability
If CFTR modulators are developed to restore chloride and bicarbonate permeability, then ion transport is improved, but the complexity of pharmaceutical development increases
Solution Approach 1:
The patent applies segmentation by dividing the CFTR modulator development into distinct structural classes (Formula I compounds with specific substituent patterns). This segmentation allows for systematic optimization of different molecular features (R1, R2, R3 substituents) to achieve desired CFTR modulatory effects, making the complex development process more manageable and predictable
Solution Approach 2:
The patent demonstrates universality by designing Formula I compounds that can address multiple CFTR mutation types (including F508del and gating mutations) with a single molecular framework. This multi-functional approach allows one compound class to treat various forms of cystic fibrosis, reducing overall development complexity compared to creating separate therapies for each mutation
Data Source
AI summary
Compounds of Formula (I) are disclosed: wherein A1, R1, R2, R3, R4, and n are as defined herein. Also disclosed is the use of the compounds in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering the compounds.