Fluorine and chlorine substituted adamantyl-urea as molecular tools for inhibition of human soluble epoxide hydrolase with picomolar efficacy

Autor: Vladimir V. Burmistrov, Christophe Morisseau, Dmitry V. Danilov, Boris P. Gladkikh, Vladimir S. D’yachenko, Nikolay A. Zefirov, Olga N. Zefirova, Gennady M. Butov, Bruce D. Hammock
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)
Druh dokumentu: article
ISSN: 14756366
1475-6374
1475-6366
00794074
DOI: 10.1080/14756366.2023.2274797
Popis: Series of 1,3-disubstituted ureas and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues were shown to inhibit human soluble epoxide hydrolase (sEH) with inhibition potency ranging from 40 pM to 9.2 nM. The measured IC50 values for some molecules were below the accuracy limit of the existing in vitro assays. Such an increase in activity was achieved by minimal structural modifications to the molecules of known inhibitors, including 4-[trans-4-(1-adamantylcarbamoylamino)cyclohexyl]oxybenzoic acid. For the chlorinated homologue of the latter the sharp jump in inhibitory activity can be (according to molecular dynamics data) the result of interactions – Cl-π interaction. Considering the extremely high inhibitory activity, acceptable solubility and partial blockage of metabolically sensitive centres in their structures, some compounds are of interest for further in vivo biotesting.
Databáze: Directory of Open Access Journals
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