Heteroaryl Disulfide Compounds for Hemoglobin Oxygen Affinity
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Solution Overview
Problem
Current allosteric effectors that increase oxygen-binding affinity of hemoglobin are limited in effectively treating sickle cell disease and high altitude tissue hypoxia, as they do not adequately prevent red blood cell sickling and oxygen delivery issues.
Innovation Solution
Development of heteroaryl disulfide compounds that bind to hemoglobin, shifting the oxygenated and deoxygenated states towards the R-state, thereby increasing oxygen-binding affinity, which are administered to red blood cells to treat sickle cell disease and improve tolerance to low oxygen environments.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current allosteric effectors are used to increase oxygen-binding affinity of hemoglobin, then oxygen loading at the lung is improved, but they fail to adequately prevent red blood cell sickling and cause oxygen delivery issues
Solution Approach 1:
The patent modifies the chemical structure of allosteric effector molecules by introducing heteroaryl disulfide groups with specific substituents (W, X, Y, Z variables representing different heteroatoms and functional groups). This structural parameter change creates compounds with optimized binding affinity that simultaneously increase oxygen loading and prevent sickling, resolving the contradiction between oxygen loading and oxygen delivery reliability.
2Stability of the object's composition
If allosteric effectors shift hemoglobin equilibrium towards the R-state, then oxygen-binding affinity increases, but the effectiveness in treating sickle cell disease is limited
Solution Approach 1:
The patent employs composite molecular structures combining heteroaryl rings with disulfide linkages and various functional groups (amino, hydroxyl, carboxyl, etc.). This composite structure allows the molecule to interact with multiple sites on hemoglobin, simultaneously stabilizing the R-state for high oxygen affinity and preventing deoxygenated HbS polymerization that causes sickling, thus addressing both parameters concurrently.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The heteroaryl disulfide compounds significantly reduce red blood cell sickling and increase oxygen delivery, as demonstrated by a marked decrease in P50 values and improved oxygen-binding affinity, effectively addressing the challenges of sickle cell disease and high altitude hypoxia.
Implementation Method 1
Allosteric effectors are small natural and synthetic molecules that bind to hemoglobin and shift the equilibrium between the oxygenated (R-state) and deoxygenated (T-state) states of hemoglobin by stabilizing the tertiary and quaternary conformations of hemoglobin.
Implementation Method 2
Under hypoxic conditions, deoxygenated HbS tetramers polymerize and distort the RBC into a sickled shape, causing occlusion and thrombosis of small blood vessels, thereby causing ischemia. Increasing the oxygen-binding affinity of sickle RBCs represents a therapeutic strategy for SCD because this increase of oxygen affinity can prevent release of oxygen and decreases the concentration of deoxygenated HbS that can polymerize causing sickling.
Data Source
AI summary
This invention relates to compounds of Formula I: (Formula I), and pharmaceutically acceptable salt thereof, which are allosteric effectors that increase the oxygen-being affinity of hemoglobin, which are useful in the treatment of sickle cell disease, high altitude tissue hypoxia, and other conditions.