Heterocyclic CFTR Stabilizers for Protein Trafficking
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Solution Overview
Problem
There is no cure for cystic fibrosis, and existing treatments are inadequate for addressing the functional deficiency of the CFTR protein, leading to severe respiratory and digestive complications due to misfolded CFTR protein retention in the endoplasmic reticulum.
Innovation Solution
Development of compounds represented by Formula (I) or (II) or their pharmaceutically acceptable salts, which can stabilize the CFTR protein and potentially correct its trafficking to the plasma membrane, thereby improving ionic homeostasis and mucociliary clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If small molecules are used to stabilize CFTR, then CFTR protein stability is improved, but the ability to correct trafficking to plasma membrane is insufficient
Solution Approach 1:
The patent modifies chemical parameters of small molecule compounds to optimize their ability to stabilize CFTR protein structure while simultaneously enhancing their capacity to correct trafficking defects. This involves adjusting molecular structure, composition, and physical-chemical properties to achieve dual functionality.
Solution Approach 2:
The invention develops composite pharmaceutical compositions containing multiple compounds or formulations that work synergistically to both stabilize CFTR protein and correct its trafficking to the plasma membrane, addressing both deficiencies of single-agent approaches.
2Object-affected harmful factors
If existing treatments are used, then some symptom relief is achieved, but functional deficiency of CFTR protein remains unaddressed
Solution Approach 1:
The patent employs compounds that act preliminarily to prevent CFTR protein misfolding and degradation before the protein can be lost, thereby maintaining functional CFTR levels at the plasma membrane to address the root cause rather than just symptoms.
Solution Approach 2:
The invention uses small molecule compounds as intermediary agents that bind to CFTR protein to stabilize its structure and facilitate proper trafficking, acting as a bridge between the misfolded protein and the cellular quality control systems to enable functional recovery.
3Stability of the object's composition
If misfolded CFTR protein is retained in endoplasmic reticulum, then protein degradation is prevented, but ionic homeostasis disruption occurs
Solution Approach 1:
The patent modifies the conformational parameters of CFTR protein through small molecule binding, enabling the protein to adopt a stable folded state that allows it to escape from endoplasmic reticulum retention and reach the plasma membrane, thereby restoring ionic homeostasis.
Data Source
AI summary
The present disclosure relates to heterocyclic compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.