ALDH2 Modulators for Ischemic Tissue Protection
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Tissues deprived of blood and oxygen undergo ischemic necrosis or infarction, and reperfusion following ischemia does not immediately return to a normal preischemic state, leading to issues like poor myocardial contractility and subcellular damage.
Innovation Solution
Development of compounds that modulate mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity, including agonists and antagonists, to treat conditions involving ischemic stress and other disorders by enhancing or inhibiting ALDH2 enzymatic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If blood flow is interrupted to treat solid tumors (induce ischemia), then tumor treatment is achieved, but tissue infarction and irreversible organ damage occur
Solution Approach 1:
The patent converts the harmful effects of ischemia (which normally cause infarction and organ damage) into beneficial effects by using ALDH2 modulators to protect tissues during ischemia-reperfusion. The modulators transform the harmful ischemic stress into a controlled therapeutic state that kills tumors while protecting normal tissues through enhanced ALDH2 activity that reduces oxidative stress and inflammation.
Solution Approach 2:
The patent changes the enzymatic activity parameter of ALDH2 by administering modulators that increase ALDH2 activity. This parameter change allows the tissue to better withstand ischemic stress and recover more effectively after reperfusion, converting the harmful ischemic state into a protected and beneficial state.
2Use of energy by moving object
If blood flow is restored after ischemia (reperfusion), then tissue oxygenation is improved, but subcellular damage and poor contractility occur
Solution Approach 1:
The patent applies preliminary action by administering ALDH2 modulators before and during ischemia-reperfusion to prepare and protect the tissue. The modulators pre-activate ALDH2 to clear toxic aldehydes and reduce oxidative stress before reperfusion occurs, preventing subcellular damage that would otherwise happen when blood flow is restored.
Solution Approach 2:
The patent uses ALDH2 modulators as intermediary substances that mediate between ischemic stress and tissue recovery. The modulators act as protective intermediaries that clear toxic metabolic products and reduce oxidative stress during the transition from ischemia to reperfusion, enabling successful tissue recovery without subcellular damage.
3Reliability
If ALDH2 activity is increased to treat ischemic disorders, then tissue recovery is improved, but compound specificity and selectivity must be maintained
Solution Approach 1:
The patent applies local quality by developing ALDH2 modulators with specific structural features that target mitochondrial ALDH2 selectively. The compounds are designed with specific molecular characteristics (such as the benzamide core structure with specific substituents) that confer high specificity for mitochondrial ALDH2 over other aldehyde dehydrogenase isoforms, ensuring reliable tissue recovery without off-target effects.
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 compounds effectively treat ischemic disorders by increasing ALDH2 activity to improve tissue recovery and reduce damage from ischemia and reperfusion, and also have applications in treating alcoholism and cancer.
Implementation Method 1
ALDH2 is an NAD+-dependent aldehyde dehydrogenase that oxidizes a broad spectrum of aldehydes, including toxic compounds, to their corresponding acids
Implementation Method 2
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is encoded in the nuclear genome and is transported into mitochondria. ALDH2 is a tetrameric protein composed of four identical subunits
Data Source
AI summary
The present invention provides compounds that function as modulators of mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity; and pharmaceutical compositions comprising the compounds. The present invention provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition. The present invention further provides assays for identifying agonists of ALDH2.