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

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

Published In Bioorg Med Chem Lett, (2020 09 15)

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.

PubMed ID: 32736212

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