Substituted Pyridines Modulate CFTR for Cystic Fibrosis
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Solution Overview
Problem
Current treatments for cystic fibrosis and related conditions, such as chronic obstructive pulmonary disease and dry eye disease, lack effective modulators for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which are essential for managing ion and fluid transport and mucus hydration.
Innovation Solution
Development of substituted pyridine compounds that act as modulators of the CFTR protein, specifically compounds of Formula I, which can be used in pharmaceutical compositions to treat cystic fibrosis and related disorders by enhancing anion secretion and improving fluid transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for cystic fibrosis are used, then existing therapeutic options are available, but effective modulators for CFTR protein are lacking
Solution Approach 1:
The patent applies parameter changes by systematically varying chemical structures of pyridine compounds (different substituents at positions R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20) to optimize CFTR modulation efficacy. This includes changing molecular weight, lipophilicity, and other physicochemical parameters to improve both reliability of CFTR binding and adaptability to treat multiple conditions including cystic fibrosis, COPD, and dry eye disease
Solution Approach 2:
The patent achieves universality by designing CFTR modulators that can treat multiple conditions caused by defective ion and fluid transport. The compounds are intended to treat not only cystic fibrosis but also chronic obstructive pulmonary disease, dry eye disease, and other conditions involving impaired anion secretion, demonstrating multi-functionality across different disease states
2Reliability
If substituted pyridine compounds are developed as CFTR modulators, then anion secretion and fluid transport are improved, but the complexity of drug development increases
Solution Approach 1:
The patent applies segmentation by dividing the CFTR modulator development into systematic components: core pyridine structure, various substituent positions (R1-R20), different salt forms, and pharmaceutical composition formulations. This structured segmentation allows methodical optimization of each component to achieve reliable ion and fluid transport function while managing development complexity through organized progression from core structure to final formulation
3Reliability
If CFTR activity is enhanced for treating cystic fibrosis, then mucus hydration and anion secretion improve, but potential off-target effects may increase
Solution Approach 1:
The patent applies feedback by implementing comprehensive preclinical testing protocols that monitor both desired effects (anion secretion, mucus hydration) and potential off-target effects. The feedback from these studies informs further compound optimization and dosing regimen selection to maximize therapeutic benefit while minimizing harmful effects, ensuring reliable treatment of cystic fibrosis and related conditions
Data Source
AI summary
The invention discloses compounds of Formula Iwherein X, R1, R2, and R3 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.