1. 1,3-Disubstituted and 1,3,3-trisubstituted adamantyl-ureas with isoxazole as soluble epoxide hydrolase inhibitors
- Author
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Burmistrov, Vladimir, Morisseau, Christophe, Danilov, Dmitry, Harris, Todd R, Dalinger, Igor, Vatsadze, Irina, Shkineva, Tatiana, Butov, Gennady M, and Hammock, Bruce D
- Subjects
Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Chemical Sciences ,Adamantane ,Drug Stability ,Enzyme Inhibitors ,Epoxide Hydrolases ,Humans ,Inhibitory Concentration 50 ,Isoxazoles ,Microsomes ,Solubility ,Structure-Activity Relationship ,Urea ,Soluble epoxide hydrolase ,Inhibitor ,Isocyanate ,Isoxazole ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.
- Published
- 2015