sEH Inhibitors Preventing EET Degradation
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Solution Overview
Problem
Current treatments for cardiovascular disorders, hypertension, heart failure, renal dysfunction, and inflammation lack effective methods to maintain elevated levels of beneficial epoxyeicosatrienoic acids (EETs) due to the degradation by soluble epoxide hydrolase (sEH), leading to inactive dihydroxyeicosatrienoic acids (DHETs).
Innovation Solution
Development of novel sEH inhibitors to prevent the degradation of EETs, thereby maintaining their beneficial vasodilatory, anti-inflammatory, and anti-thrombotic effects, which are used in pharmaceutical compositions for treating conditions mediated by the sEH enzyme.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sEH enzyme activity is not inhibited, then EETs are converted to DHETs through hydrolysis, but the beneficial vasodilatory, anti-inflammatory, and anti-thrombotic effects of EETs are lost
Solution Approach 1:
The patent applies this principle by targeting the sEH enzyme that causes EET degradation and converting this harmful metabolic pathway into a beneficial therapeutic opportunity. By designing inhibitors that specifically block sEH activity, the naturally occurring degradation process is halted, allowing EETs to accumulate and exert their protective effects. This transforms the enzyme's harmful function into a therapeutic target, enabling treatment of cardiovascular disorders through selective enzymatic inhibition.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of compounds to optimize their inhibition of sEH. The invention describes specific molecular structures with varying substituents (R1, R2, R3, R4, R5, R6, R7, R8 groups) that can be adjusted to enhance binding affinity and selectivity for sEH. By systematically varying these chemical parameters, the patent achieves compounds with improved potency and selectivity, thereby effectively preventing EET degradation while minimizing off-target effects.
2Reliability
If broad-spectrum epoxide hydrolase inhibitors are used, then both sEH and mEH activities are inhibited, but the detoxification pathway provided by mEH is blocked
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific molecular characteristics that enable selective binding to sEH while sparing mEH. The invention describes compounds with particular structural features (such as aromatic rings with specific substituents, amine groups, and hydroxyl groups at defined positions) that create local chemical environments complementary to the sEH active site. This localized molecular design ensures that only sEH is inhibited, preserving mEH's essential detoxification function while achieving therapeutic EET protection.
Solution Approach 2:
The patent employs the intermediary principle by introducing highly selective sEH inhibitors as molecular mediators that specifically bridge the interaction between the drug and the sEH enzyme without affecting mEH. These inhibitor compounds act as selective intermediaries that recognize and bind to unique features of the sEH active site, thereby blocking EET degradation while leaving the mEH detoxification pathway intact. This selective intermediary action resolves the contradiction between EET protection and detoxification preservation.
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 sEH inhibitors effectively inhibit the activity of soluble epoxide hydrolase, allowing EETs to accumulate and exert their protective effects against various cardiovascular and inflammatory disorders, providing a therapeutic approach to manage conditions such as hypertension and inflammation.
Implementation Method 1
The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme... sEH converts EETs into dihydroxyeicosatrienoic acids (DHETs)... Pharmacological, knockout mouse phenotype and genetic polymorphism studies suggest that elevated EET levels are protective in numerous cardiovascular disorders
Data Source
AI summary
The invention is directed to novel sEH inhibitors and their use in the treatment of diseases mediated by the sEH enzyme.