1. 1,3-Disubstituted and 1,3,3-trisubstituted adamantyl-ureas with isoxazole as soluble epoxide hydrolase inhibitors.
- Author
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Burmistrov V, Morisseau C, Danilov D, Harris TR, Dalinger I, Vatsadze I, Shkineva T, Butov GM, and Hammock BD
- Subjects
- Adamantane pharmacology, Drug Stability, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Isoxazoles pharmacology, Microsomes chemistry, Microsomes drug effects, Solubility, Structure-Activity Relationship, Adamantane chemistry, Epoxide Hydrolases antagonists & inhibitors, Isoxazoles chemistry, Urea chemistry, Urea pharmacology
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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