Macrocyclic CFTR Modulator Combinations for Folding and Trafficking
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Solution Overview
Problem
Current treatments for CFTR-related diseases, particularly cystic fibrosis, are limited in effectively addressing the dysfunctional CFTR protein caused by various mutations, leading to organ dysfunction due to impaired chloride and bicarbonate transport, with existing CFTR modulators showing limitations in efficacy and safety profiles.
Innovation Solution
Combination therapy using macrocyclic CFTR modulators, specifically CFTR correctors and potentiators, to enhance CFTR protein folding, trafficking, and function, targeting different binding sites on the CFTR protein to achieve synergistic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CFTR modulators are used to treat CFTR-related diseases, then some therapeutic effect is achieved, but efficacy and safety profiles are limited
Solution Approach 1:
The invention segments the CFTR modulator therapy into distinct functional categories (type-I correctors, type-II correctors, type-III correctors, and potentiators), each targeting specific aspects of CFTR dysfunction. This segmentation allows for more precise and effective treatment by addressing different mechanisms of CFTR defect separately and in combination, thereby improving overall therapeutic efficacy while managing safety through targeted action.
Solution Approach 2:
The invention combines multiple CFTR modulators with different mechanisms of action into composite treatment regimens. By merging type-I correctors, type-II correctors, type-III correctors, and potentiators in specific combinations, the therapy achieves synergistic effects that enhance CFTR function more effectively than single agents, while the combined formulations are designed to optimize safety profiles through balanced pharmacological action.
2Reliability
If CFTR modulators target different binding sites on CFTR protein, then synergistic effects are achieved, but treatment complexity increases
Solution Approach 1:
The CFTR modulators are segmented into distinct functional classes (type-I, type-II, type-III correctors and potentiators), each with specific binding sites and mechanisms of action. This segmentation enables targeted interaction with different regions of the CFTR protein, achieving synergistic effects through coordinated action while maintaining clear differentiation between drug classes to manage treatment complexity.
Solution Approach 2:
The invention utilizes parameter changes in terms of dosing regimens, pharmacokinetic profiles, and binding affinities to optimize the combination of CFTR modulators. By adjusting these parameters, the therapy achieves synergistic effects at different binding sites while maintaining manageable treatment complexity through optimized dosing schedules and pharmacological parameters.
Data Source
AI summary
The present invention concerns the compounds of formula (I) wherein R1, R2, R3, R4, X, Ar1 and Ar2 are as described in the description, and their use in the treatment of CFTR-related diseases and disorders, especially in the treatment of cystic fibrosis, in combination with one or more therapeutically active ingredients acting as CFTR modulator(s), wherein said CFTR modulator(s) is/are CFTR one or more CFTR corrector(s) and/or a CFTR potentiator. The invention further relates to pharmaceutical compositions comprising the compounds of formula (I) in combination with one or more therapeutically active ingredients acting as CFTR modulator(s), wherein said CFTR modulator(s) is/are one or more CFTR corrector(s) and/or a CFTR potentiator.