sEH Inhibitors Preventing EET Degradation
Find Innovative SolutionsGenerate Solutions
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 mediated by soluble epoxide hydrolase (sEH), leading to inactive dihydroxyeicosatrienoic acids (DHETs).
Innovation Solution
Development of novel sEH inhibitors, represented by specific compounds according to Formula I, which inhibit the activity of sEH, thereby preventing the degradation of EETs and maintaining their beneficial effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sEH activity is not inhibited, then EETs are converted to DHETs by sEH, but the beneficial vasodilatory, anti-inflammatory, and anti-thrombotic effects of EETs are lost
Solution Approach 1:
The patent converts the harmful degradation pathway into a beneficial therapeutic effect by designing sEH inhibitors that block the conversion of EETs to DHETs. The inhibitors transform the enzyme's natural substrate specificity against us into a therapeutic mechanism, where blocking sEH activity preserves EETs and produces beneficial cardiovascular effects.
Solution Approach 2:
The patent introduces sEH inhibitors as intermediary compounds that mediate between EETs and sEH. These compounds bind to sEH and prevent substrate access, acting as a protective intermediary layer that preserves EET levels without requiring direct modification of the enzyme or substrate.
2Reliability
If compounds are designed to inhibit sEH, then EET degradation is prevented, but selective inhibition of sEH over mEH is challenging
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features that target the unique active site architecture of sEH. The inhibitors incorporate functional groups and molecular configurations that complement sEH's binding pocket geometry and electrostatic properties, providing selective inhibition without affecting mEH.
Solution Approach 2:
The patent utilizes parameter changes by modifying compound properties such as molecular size, shape, and functional group arrangement to achieve selective sEH inhibition. By adjusting these parameters, the compounds optimize binding affinity for sEH while maintaining selectivity against mEH and other epoxide hydrolases.
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 treat diseases associated with sEH by maintaining elevated EET levels, providing therapeutic benefits for conditions like hypertension, heart failure, and inflammation by preventing the conversion of EETs to inactive DHETs.
Implementation Method 1
soluble epoxide hydrolase ('sEH') is primarily responsible for the metabolism of arachidonic acid derivatives known as epoxyeicosatrienoic acids ('EETs'). sEH converts EETs into dihydroxyeicosatrienoic acids ('DHETs').
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. Specifically, the invention is directed to compounds according to Formula I: wherein R1, R2, R4, R5, R6, A, B, Y, Z, n, and m are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are sEH inhibitors and can be used in the treatment of diseases mediated by the sEH enzyme, such as hypertension. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting sEH and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.