Imidazolidine-2,4,5- and pirimidine-2,4,6-triones - New primary pharmacophore for soluble epoxide hydrolase inhibitors with enhanced water solubility

Vladimir Burmistrov; Christophe Morisseau; Vladimir D'yachenko; Dmitry Karlov; Gennady M Butov; Bruce D Hammock

doi:10.1016/j.bmcl.2019.126908

Imidazolidine-2,4,5- and pirimidine-2,4,6-triones - New primary pharmacophore for soluble epoxide hydrolase inhibitors with enhanced water solubility

Bioorg Med Chem Lett. 2020 Feb 1;30(3):126908. doi: 10.1016/j.bmcl.2019.126908. Epub 2019 Dec 18.

Authors

Vladimir Burmistrov¹, Christophe Morisseau², Vladimir D'yachenko³, Dmitry Karlov⁴, Gennady M Butov³, Bruce D Hammock⁵

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 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 imidazolidine-2,4,5-trione or pirimidine-2,4,6-trione has been synthesized. Inhibition potency of the described compounds ranges from 8.4 μM to 0.4 nM. The tested compounds possess higher water solubility than their preceding ureas. Molecular docking indicates new bond between the triones and the active site of sEH that in part explain the observed potency of the new pharmacophores. While less potent than the corresponding ureas, the modifications of urea group reported herein yield compounds with higher water solubility, thus permitting easier formulation.

Keywords: Adamantane; Epoxyeicosatrienoic acids; Imidazolidine-2,4,5-trione; Inhibitor; Pirimidine-2,4,6-trione; Soluble epoxide hydrolase; Urea.

Publication types

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

MeSH terms

Adamantane / chemistry
Adamantane / metabolism
Binding Sites
Catalytic Domain
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Epoxide Hydrolases / antagonists & inhibitors*
Epoxide Hydrolases / metabolism
Humans
Imidazolidines / chemistry*
Imidazolidines / metabolism
Inhibitory Concentration 50
Molecular Docking Simulation
Pyrimidines / chemistry*
Pyrimidines / metabolism
Solubility
Structure-Activity Relationship
Urea / chemistry
Urea / metabolism

Substances

Enzyme Inhibitors
Imidazolidines
Pyrimidines
Urea
Epoxide Hydrolases
pyrimidine
Adamantane

Abstract

Publication types

MeSH terms

Substances

Grants and funding