Adamantyl thioureas as soluble epoxide hydrolase inhibitors

Vladimir Burmistrov; Christophe Morisseau; Dmitry Pitushkin; Dmitry Karlov; Robert R Fayzullin; Gennady M Butov; Bruce D Hammock

doi:10.1016/j.bmcl.2018.05.024

Adamantyl thioureas as soluble epoxide hydrolase inhibitors

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2302-2313. doi: 10.1016/j.bmcl.2018.05.024. Epub 2018 May 23.

Authors

Vladimir Burmistrov¹, Christophe Morisseau², Dmitry Pitushkin³, Dmitry Karlov⁴, Robert R Fayzullin⁵, Gennady M Butov³, Bruce D Hammock⁶

Affiliations

¹ Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA; Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch) Volgograd State Technical University, Volzhsky 404121, Russia.
² Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
³ Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch) Volgograd State Technical University, Volzhsky 404121, Russia.
⁴ Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Moscow 143026, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region 142432, Russia.
⁵ Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of Russian Academy of Sciences, Kazan 420088, Russia.
⁶ Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. Electronic address: bdhammock@ucdavis.edu.

Abstract

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.

Keywords: Adamantane; Inhibitor; Isothiocyanate; Soluble epoxide hydrolase; Thiourea.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adamantane / analogs & derivatives*
Adamantane / chemical synthesis
Adamantane / pharmacology*
Animals
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Epoxide Hydrolases / antagonists & inhibitors*
Humans
Mice
Models, Chemical
Molecular Docking Simulation
Quantum Theory
Rats
Solubility
Thiourea / analogs & derivatives*
Thiourea / chemical synthesis
Thiourea / pharmacology*

Substances

Enzyme Inhibitors
Epoxide Hydrolases
EPHX2 protein, human
EPHX2 protein, rat
Ephx2 protein, mouse
Thiourea
Adamantane

Abstract

Publication types

MeSH terms

Substances

Grants and funding