Design, Synthesis, and Biological Activity of 1,3-Disubstituted Ureas as Potent Inhibitors of the Soluble Epoxide Hydrolase of Increased Water Solubility

In Hae Kim, Christophe Morisseau, Takaho Watanabe, Bruce D. Hammock

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

The soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas are potent inhibitors of sEH that are active both in vitro and in vivo. However, their poor solubility in either water or lipid reduces their in vivo efficacy and makes them difficult to formulate. To improve these physical properties, the effect of incorporating polar functional groups into one of the alkyl chains was evaluated on their inhibitor potencies, water solubility, octanol/water partition coefficients (log P), and melting points. No loss of inhibition potency was observed when a polar functional group was incorporated at least five atoms (∼7.5 Å) from the central urea carbonyl. In addition, the presence of a polar group at least 11 atoms away from the urea carbonyl group for the mouse and human sEHs, respectively, did not alter the inhibitor potency. The resulting compounds have better water solubility and generally lower log P values and melting points than nonfunctionalized liphophilic ureas. These properties will make the compounds more bioavailable and more soluble in either water- or oil-based formulations.

Original languageEnglish (US)
Pages (from-to)2110-2122
Number of pages13
JournalJournal of Medicinal Chemistry
Volume47
Issue number8
DOIs
StatePublished - Apr 8 2004

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Epoxide Hydrolases
Bioactivity
Solubility
Urea
Water
Functional groups
Freezing
Melting point
Pressure regulation
Octanols
Atoms
Blood pressure
Metabolism
Oils
Physical properties
Blood Pressure
Inflammation
Lipids

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, Synthesis, and Biological Activity of 1,3-Disubstituted Ureas as Potent Inhibitors of the Soluble Epoxide Hydrolase of Increased Water Solubility. / Kim, In Hae; Morisseau, Christophe; Watanabe, Takaho; Hammock, Bruce D.

In: Journal of Medicinal Chemistry, Vol. 47, No. 8, 08.04.2004, p. 2110-2122.

Research output: Contribution to journalArticle

Kim, In Hae ; Morisseau, Christophe ; Watanabe, Takaho ; Hammock, Bruce D. / Design, Synthesis, and Biological Activity of 1,3-Disubstituted Ureas as Potent Inhibitors of the Soluble Epoxide Hydrolase of Increased Water Solubility. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 8. pp. 2110-2122.
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