1,3-Disubstituted and 1,3,3-trisubstituted adamantyl-ureas with isoxazole as soluble epoxide hydrolase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Burmistrov, Vladimir^1,2,3  Morisseau, Christophe^1,2  Danilov, Dmitry³  Harris, Todd R.^1,2  Dalinger, Igor⁴  Vatsadze, Irina⁴  Shkineva, Tatiana⁴  Butov, Gennady M.³  Hammock, Bruce D.^1,2 

[1] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA

[2] Univ Calif Davis, UC Davis Comprehens Canc Ctr, Davis, CA 95616 USA

[3] Volgograd State Tech Univ, Volzhsky Polytech Inst Branch, Dept Chem Technol & Equipment Chem Ind, Volzhsky, Russia

[4] Russian Acad Sci, ND Zelinsky Inst Organ Chem ZIOC, Moscow, Russia

关键词: Soluble epoxide hydrolase;    Inhibitor;    Adamantane;    Isocyanate;    Urea;    Isoxazole;   

DOI  :  10.1016/j.bmcl.2015.10.066

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Ltd. All rights reserved.

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