Memantine Urea Derivatives for Selective sEH Inhibition
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Solution Overview
Problem
Current methods for treating pain, particularly inflammatory and neuropathic pain, have dose-dependent side effects and limited efficacy, necessitating the development of novel sEH inhibitors to stabilize endogenous bioactive lipids and reduce inflammatory mediators.
Innovation Solution
Development of memantyl urea derivatives with specific structural formulas that act as potent inhibitors of soluble epoxide hydrolase (sEH), effectively reducing pain and inflammation by modulating the levels of EpFA metabolites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current pain treatment methods are used, then pain relief is achieved, but dose-dependent side effects occur
Solution Approach 1:
The patent develops novel sEH inhibitor compounds with optimized molecular structures (Formulas 1 and 2 with various substituent groups) to achieve selective inhibition of soluble epoxide hydrolase. This parameter change in the chemical structure allows for effective pain relief through stabilization of endogenous bioactive lipids while reducing side effects associated with conventional analgesics
2Reliability
If sEH inhibition is increased to reduce inflammatory mediators, then anti-inflammatory effect is improved, but risk of affecting COX pathway increases
Solution Approach 1:
The patent employs selective sEH inhibition as an intermediary mechanism to reduce inflammatory mediators. The developed compounds specifically target sEH enzyme without significantly affecting COX pathway, thereby achieving anti-inflammatory effects through stabilization of epoxyeicosatrienoic acids (EETs) while avoiding the thrombosis risk associated with COX inhibition
3Reliability
If conventional NSAIDs are used to treat inflammatory pain, then pain relief is achieved, but thrombosis side effects occur
Solution Approach 1:
The patent extracts and isolates the beneficial anti-inflammatory and analgesic effects from the harmful thrombosis side effects by selectively targeting sEH inhibition. The developed compounds achieve pain relief through sEH inhibition without the thrombosis risk associated with conventional NSAIDs that affect COX pathway
Data Source
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AI summary
The present application provides a memantine urea derivative, a preparation method therefor, and use thereof, which relate to the technical field of pharmaceutics. The memantine urea derivative provided by the present application has a typical urea structure as a primary pharmacophore of sEH. Molecular docking shows that the memantine moiety acts as a hydrophobic fragment to generate hydrophobic interactions with a receptor. Notably, when R1 and R2 are all methyl groups (i.e., 3,5-dimethyl substitution), the van der Waals force can be enhanced. Therefore, the memantine urea derivative provided by the present application has high inhibitory activity against human sEH (HsEH) and murine sEH (MsEH), and can be used as an sEH inhibitor for preparing a medicament for treating a soluble epoxide enzyme-mediated disease.