Polynitrogen-containing compounds as multi-target sEH/FAAH inhibitors: Structure-activity relationship and...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) degrade anti-inflammatory lipids.
• Inhibiting sEH and FAAH is a promising strategy for non-opioid pain management.
• Previous work identified a pharmacophore for dual sEH/FAAH inhibition.

Purpose of the Study:

• To synthesize and evaluate novel heterocyclic analogs for dual sEH and FAAH inhibition.
• To improve metabolic stability and solubility while maintaining high inhibitory potency.
• To explore the structure-activity relationships of new dual inhibitors.

Main Methods:

• Synthesis of 18 analogs featuring pyrimidinyl, quinoxalinyl, and tetrazolyl rings.
• In vitro enzyme inhibition assays against human FAAH and human, rat, and mouse sEH.
• Receptor binding assays, liver microsome stability tests, and in vivo wheel running assay.

Main Results:

• Quinoxalinyl analog 4m emerged as the most potent dual inhibitor to date (nM IC50 values).
• 4m demonstrated selectivity, with no significant binding to opioid or most serotonin receptors.
• In vivo studies showed 4m reduced locomotor activity, similar to morphine, indicating potential behavioral effects.

Conclusions:

• Analog 4m represents a highly potent dual sEH/FAAH inhibitor with potential for non-opioid pain therapies.
• Further investigation is needed to understand and mitigate the observed behavioral effects of 4m.
• The study highlights the therapeutic potential of dual sEH/FAAH inhibition for inflammatory pain.