Substituted Tricyclic Compounds for CFTR Modulation
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Solution Overview
Problem
Current treatments for cystic fibrosis and related disorders lack effective modulators for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which are essential for addressing defective protein trafficking and ion transport issues leading to respiratory and gastrointestinal problems.
Innovation Solution
Development of substituted tricyclic compounds that act as CFTR modulators, specifically compounds of formula (I) and their pharmaceutical compositions, designed to enhance CFTR activity and anion secretion, thereby treating cystic fibrosis and other CFTR-related disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for cystic fibrosis, then current standard therapies are administered, but effective modulators for CFTR protein are lacking
Solution Approach 1:
The patent employs parameter changes by systematically varying chemical structures of tricyclic compounds (modifying R1, R2, R3, G1, m, Z parameters) to optimize CFTR modulation efficacy. This allows tuning of compound properties to effectively address different CFTR protein defects while maintaining reliable therapeutic action.
Solution Approach 2:
The invention segments the complex CFTR modulation problem into specific molecular interactions by designing compounds with distinct functional regions (G1 group, R1-R3 substituents, tricyclic core). This segmentation enables targeted binding to different CFTR defect types, improving both reliability and adaptability of treatment.
2Productivity
If CFTR modulators are developed to improve anion secretion, then ion transport is enhanced, but new compound classes must be synthesized and tested
Solution Approach 1:
The patent achieves universality by designing a core tricyclic compound structure (formula I) that can perform multiple functions: enhancing anion secretion, modulating CFTR activity, and treating various CFTR-related disorders. The standardized core structure with variable substituents enables broad therapeutic application while simplifying manufacturing through a common synthesis platform.
Solution Approach 2:
The invention uses copying by establishing a proven tricyclic core structure (formula I) that can be replicated with different substituent patterns (R1, R2, R3, G1, m, Z variations). This copying approach allows systematic optimization of CFTR modulation while maintaining ease of manufacture through established synthetic routes for the core structure.
3Reliability
If substituted tricyclic compounds are used as CFTR modulators, then CFTR activity is improved, but specific structural parameters must be optimized
Solution Approach 1:
The patent systematically applies parameter changes by defining specific ranges and options for structural parameters (R1 as halogen/alkyl/ORj/SRj, R2 as hydrogen/alkyl, R3 with specific formulas, G1 as phenyl/heteroaryl/cycloalkyl, m as 0-4, Z as O/N(Rz1)). This structured parameter optimization ensures reliable CFTR modulation while providing clear manufacturing specifications.
Solution Approach 2:
The invention applies local quality by allowing different substituent patterns at specific positions (R1-R3, G1, Z) to optimize local interactions with CFTR protein variants. This enables tailored molecular properties at specific locations while maintaining overall structural integrity, achieving both reliable efficacy and precise manufacturing control.
Data Source
AI summary
The present invention provides for compounds of formula (I)wherein R1, m, Z, G1, R2, and R3 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).