Reversible Succinate Dehydrogenase Inhibitors for Reperfusion Injury
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current succinate dehydrogenase inhibitors for treating reperfusion injury are either irreversible or not cell-permeable, limiting their effectiveness in preventing succinate accumulation and subsequent reactive oxygen species production.
Innovation Solution
A cell-permeable, reversible succinate dehydrogenase inhibitor, such as dimethyl malonate, which inhibits succinate accumulation and is metabolized to malonate within cells, reducing reperfusion injury by selectively targeting succinate metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If irreversible complex II inhibitors (such as 3-nitropropionate and atpennin A5) are used to protect against ischemia-reperfusion injury, then cardioprotection is achieved, but the inhibitors permanently prevent complex II from carrying out its normal function
Solution Approach 1:
The patent changes the chemical nature of the inhibitor from irreversible to reversible by using malonate and its derivatives, which form reversible complexes with succinate dehydrogenase. This allows the enzyme to regain function after inhibition, preventing permanent inactivation while maintaining protective effects during ischemia-reperfusion injury.
2Reliability
If malonate is used as a complex II inhibitor, then it provides some cardioprotective effect, but it requires millimolar concentrations and is not cell-permeable
Solution Approach 1:
The patent modifies malonate by adding lipophilic groups (such as aromatic rings and alkyl chains) to create derivatives that can cross cell membranes. These structural modifications change the physicochemical parameters of the molecule, enabling cell permeability while maintaining inhibitory activity against succinate dehydrogenase at lower concentrations.
Solution Approach 2:
The patent uses ester prodrugs (such as dimethyl malonate and diethyl malonate) as intermediaries that can cross cell membranes more easily. These prodrugs are then hydrolyzed intracellularly to release the active malonate derivative, enabling targeted delivery and reducing the required concentration.
3Reliability
If high concentrations of malonate are used to achieve inhibition, then succinate dehydrogenase is inhibited, but the required millimolar levels reduce therapeutic index and increase side effects
Solution Approach 1:
The patent uses structural modifications to increase the potency of malonate derivatives, allowing effective inhibition at lower concentrations. The added aromatic and lipophilic groups enhance binding affinity to succinate dehydrogenase, reducing the concentration required for effective inhibition and thereby decreasing toxicity.
Solution Approach 2:
The patent employs ester prodrugs as intermediaries that can be administered at lower doses. These prodrugs are converted to active inhibitors within cells, providing targeted therapy and reducing systemic exposure and side 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 inhibitor effectively decreases succinate levels during ischemia, reducing reactive oxygen species production and minimizing tissue damage during reperfusion, with low toxicity and rapid metabolism to avoid side effects.
Implementation Method 1
The prodrug dimethyl malonate will be hydrolysed in vivo to malonate which is an inhibitor of SDH
Implementation Method 2
malonate and derivatives thereof which are membrane permeable and are reversible inhibitors of complex II
Data Source
Figure 1a~1c
Figure 1d~1e
Figure 1f~1i
AI summary
The invention relates to a succinate dehydrogenase inhibitor or a prodrug and/or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of reperfusion injury, such as ischemia-reperfusion injury, by inhibiting the accumulation of succinate, wherein the inhibitor or prodrug and/or pharmaceutically acceptable salt thereof is a cell-permeable reversible inhibitor of succinate dehydrogenase.