CFTR Modulator Compounds for F508del Trafficking and Gating Defects
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Solution Overview
Problem
Current treatments for cystic fibrosis, particularly those targeting the F508del mutation in the CFTR protein, show limited efficacy, necessitating the development of customized modulators for different genetic sub-groups of patients.
Innovation Solution
Novel compounds, such as those of Formula (Ia) and their pharmaceutically acceptable salts, hydrates, and solvates, are designed to modulate CFTR protein activity, addressing trafficking and gating defects by correcting and potentiating the function of mutated CFTR proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CFTR modulators are used to treat cystic fibrosis, then some therapeutic effect is achieved, but the efficacy is limited and does not sufficiently improve respiratory function
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of CFTR modulators through various substituents (R1-R6 groups) to optimize their binding affinity and functional efficacy. By systematically varying molecular parameters such as substituent types, positions, and configurations, the invention achieves enhanced therapeutic effect and respiratory function improvement compared to existing modulators
Solution Approach 2:
The patent employs composite material principles by creating complex molecular structures that combine multiple functional groups and structural elements. The CFTR modulators incorporate diverse chemical moieties (heterocyclic rings, aromatic groups, aliphatic chains) that work synergistically to correct CFTR trafficking and gating defects, resulting in superior therapeutic performance
2Adaptability or versatility
If generic CFTR modulators are used, then broad applicability is achieved, but customized treatment for different genetic sub-groups is insufficient
Solution Approach 1:
The patent applies local quality by designing CFTR modulators with specific molecular features tailored to address particular CFTR mutation characteristics. Different substituents and structural elements are strategically placed to target specific genetic sub-groups, enabling customized treatment approaches that match the specific pathological mechanisms of each patient population
Solution Approach 2:
The patent embodies dynamics by creating a flexible molecular framework that can adapt to different CFTR mutation types. The modular chemical structure allows for dynamic adjustment of pharmacological properties to match varying genetic profiles, transitioning from static generic treatments to dynamic customized therapies
Data Source
AI summary
The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular to modulate CFTR protein or ABC protein activities.