ABC Transporter Modulators for Cystic Fibrosis Treatment
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Solution Overview
Problem
Current treatments for ABC transporter-mediated diseases, such as cystic fibrosis, lack effective modulators to address defective protein trafficking and activity, leading to impaired ion and fluid transport, and there is a need for compounds that can modulate ABC transporter activity to treat a wide range of diseases beyond cystic fibrosis.
Innovation Solution
Development of compounds, including compound 322, which act as modulators of ABC transporter activity, particularly CFTR, to increase or decrease activity, thereby treating various diseases by enhancing or reducing anion secretion, thereby addressing defective protein trafficking and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for ABC transporter-mediated diseases are used, then disease management is maintained, but effective modulation of defective protein trafficking and activity is not achieved
Solution Approach 1:
The patent develops a series of compounds (including compound 322 and related structures) that can modulate multiple ABC transporters including CFTR, MDR1, and MRP1. The compounds share common structural features (such as the core scaffold with specific substituent patterns) that enable broad-spectrum activity across different transporter families, allowing a single compound class to address multiple diseases and transporter defects simultaneously.
2Productivity
If compounds are developed to modulate ABC transporter activity, then anion secretion and ion transport are improved, but the complexity of identifying effective modulators for specific transporters increases
Solution Approach 1:
The patent systematically varies key structural parameters of the modulator compounds, including substituent types (R1, R2, R3 groups), ring structures, and molecular weight ranges. By establishing structure-activity relationship (SAR) patterns, the invention identifies specific parameter ranges that optimize binding to ABC transporters while maintaining desired pharmacological effects, thereby reducing the complexity of compound identification through rational design rather than exhaustive screening.
Solution Approach 2:
The patent employs iterative optimization where initial compound screening provides feedback on which structural features confer desired activity. This feedback is used to refine the compound series, with subsequent generations of compounds incorporating successful features and eliminating ineffective ones. The process continues until optimal modulators are identified, balancing efficacy with reduced screening complexity.
Data Source
AI summary
Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette ('ABC') transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator ('CFTR'). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.