Title: Imidazolidine-2,4,5- and pirimidine-2,4,6-triones - New primary pharmacophore for soluble epoxide hydrolase inhibitors with enhanced water solubility.
Authors: Burmistrov, Vladimir; Morisseau, Christophe; D'yachenko, Vladimir; Karlov, Dmitry; Butov, Gennady M; Hammock, Bruce D
Published In Bioorg Med Chem Lett, (2020 02 01)
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.
PubMed ID: 31870649
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