Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors
Sung Hee Hwang1, Christophe Morisseau, Zung Do
1Department of Entomology and UCD Cancer Center, University of California, One Shields Avenue, Davis, CA 95616-8584, USA.
Bioorganic & Medicinal Chemistry Letters
|September 5, 2006
Summary
Researchers synthesized novel urea inhibitors targeting soluble epoxide hydrolase (sEH). Simple carbocyclic and phenyl groups demonstrated potent inhibition, outperforming adamantane analogs. Bulky or ionizable substituents reduced inhibitory activity.
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibition
- Drug Discovery
Background:
- Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxyeicosatrienoic acids.
- Dysregulation of sEH activity is implicated in various pathological conditions, including inflammation and cardiovascular diseases.
- Development of potent and selective sEH inhibitors is a significant therapeutic goal.
Purpose of the Study:
- To synthesize and evaluate a library of N,N'-disubstituted urea compounds as potential inhibitors of human soluble epoxide hydrolase.
- To explore the structure-activity relationships of urea-based sEH inhibitors.
- To identify novel scaffolds with improved inhibitory profiles compared to existing adamantane-based inhibitors.
Main Methods:
- Solid-phase synthesis was employed to generate a diverse library of 192 N,N'-disubstituted urea analogs.
- Inhibitory activities of the synthesized compounds were assessed against recombinant human soluble epoxide hydrolase (sEH).
- Structure-activity relationships were analyzed by varying carbocyclic and phenyl substituents on the urea core.
Main Results:
- Several N,N'-disubstituted ureas exhibited significant inhibitory activity against sEH.
- Compounds featuring simple carbocyclic or para/meta-substituted phenyl groups displayed inhibition potencies comparable to or exceeding those of adamantane-based sEH inhibitors.
- Introduction of bulky or ionizable functional groups adjacent to the urea moiety resulted in a marked decrease in inhibitory efficacy.
Conclusions:
- N,N'-disubstituted ureas represent a promising class of soluble epoxide hydrolase inhibitors.
- Strategic placement of simple, non-ionizable substituents is crucial for potent sEH inhibition.
- The identified urea scaffolds offer a valuable starting point for the development of new therapeutics targeting sEH-related diseases.
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