Pyrazolyl Amide Compounds for CFTR Protein Folding and Chloride Transport
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Solution Overview
Problem
There is a need for compounds and methods to increase cystic fibrosis transmembrane conductance regulator (CFTR) activity and treat CFTR-related diseases, particularly those associated with protein misfolding, such as cystic fibrosis, where mutations like ΔF508 disrupt protein folding and trafficking, leading to degraded CFTR function.
Innovation Solution
The development of specific compounds, represented by Formulas (IV) and (V), and their pharmaceutically acceptable salts, stereoisomers, and prodrugs, which are administered to enhance CFTR activity in human bronchial epithelial cells, including those with mutant CFTR proteins like ΔF508, by increasing chloride channel activity and ion transport.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CFTR modulators are used, then CFTR activity is improved, but manufacturing complexity and development time increase due to the need for multiple compound classes
Solution Approach 1:
The patent applies universality by designing a single compound structure (Formula I) that can function as multiple types of CFTR modulators. The core pyrimidine or pyridine ring with specific substituents allows the compound to act as a corrector, potentiator, or amplifier depending on its molecular configuration, eliminating the need for separate compound classes for each modulator type.
Solution Approach 2:
The patent uses parameter changes by systematically varying substituents at specific positions (R1-R6, X1-X2, Y1-Y2) on the core ring structure to tune the compound's pharmacological properties. By changing these molecular parameters, the same base structure can be optimized for different CFTR modulation mechanisms, simplifying the overall therapeutic approach.
2Reliability
If multiple CFTR modulator types are developed separately, then comprehensive CFTR function restoration is achieved, but development time and resource allocation increase
Solution Approach 1:
The patent merges the functions of multiple CFTR modulator types into a single compound class. By combining the structural features necessary for corrector, potentiator, and amplifier activities into one molecular framework (Formula I), the patent enables simultaneous optimization of all three modulation mechanisms through a unified development program rather than separate parallel programs.
Solution Approach 2:
The patent applies preliminary action by establishing a comprehensive structure-activity relationship (SAR) framework upfront that accounts for all three modulator types. This preliminary structural design allows researchers to predict and optimize compound behavior across different modulation mechanisms before entering clinical trials, reducing the need for extensive late-stage optimization.
3Reliability
If complex multi-mechanism modulators are designed, then comprehensive CFTR restoration is achieved, but synthesis difficulty and manufacturing complexity increase
Solution Approach 1:
The patent applies segmentation by dividing the complex modulator function into distinct molecular segments or substituents (R1-R6 groups, X1-X2 heteroatoms, Y1-Y2 attachments) on the core ring structure. Each segment can be independently optimized and synthesized using standard organic chemistry techniques, then assembled into the final compound, simplifying the overall manufacturing process compared to creating entirely new complex molecules.
Data Source
AI summary
The present disclosure is based, in part, on the discovery that disclosed compounds such as those having Formula (IVa), (Va), (IV), or (V) can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells.