Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

Vladimir Burmistrov; Christophe Morisseau; Dmitry Karlov; Dmitry Pitushkin; Andrey Vernigora; Elena Rasskazova; Gennady M Butov; Bruce D Hammock

doi:10.1016/j.bmcl.2020.127430

Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127430. doi: 10.1016/j.bmcl.2020.127430. Epub 2020 Jul 24.

Authors

Vladimir Burmistrov¹, Christophe Morisseau², Dmitry Karlov³, Dmitry Pitushkin⁴, Andrey Vernigora⁵, Elena Rasskazova⁵, Gennady M Butov⁶, Bruce D Hammock⁷

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; School of Chemistry, Volgograd State Technical University, Volgograd 400131, Russia.
² Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
³ 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.
⁴ Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (branch) Volgograd State Technical University, Volzhsky 404121, Russia; School of Chemistry, Volgograd State Technical University, Volgograd 400131, Russia.
⁵ School of Chemistry, Volgograd State Technical University, Volgograd 400131, Russia.
⁶ Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (branch) Volgograd State Technical University, Volzhsky 404121, Russia.
⁷ 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 lipophilic groups of natural origin (camphanyl, norcamphanyl, furan-2-yl) were developed. Inhibitory potency ranging from 0.4 nM to 2.16 μM were obtained. While having the same level of inhibitory activity bicyclic ureas are up to 10-fold more soluble than the corresponding ureas containing adamantyl or 4-trifluoromethoxyphenyl substituents. This makes them easier to formulate, more bioavailable and thus more promising as therapeutic sEH inhibitors. Endo/exo-form of compound 2b derived from l-camphor is 14-fold more potent than the corresponding analogue derived from d-camphor (IC₅₀ = 3.7 nM vs. 50.6 nM) indicating enantiomeric preference.

Keywords: Adamantane; Camphor; Inhibitor; Norcamphane; 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
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Epoxide Hydrolases / antagonists & inhibitors*
Humans
Lipids / chemistry*
Molecular Docking Simulation
Protein Binding
Solubility
Stereoisomerism
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Water

Substances

Enzyme Inhibitors
Lipids
Water
Urea
Epoxide Hydrolases
Adamantane

Abstract

Publication types

MeSH terms

Substances

Grants and funding