Structure-based optimization of the piperazino-containing 1,3 -disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase

Shao Xu Huang, Bin Cao, Christophe Morisseau, Yi Jin, Bruce D. Hammock, Ya Qiu Long

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of cardiovascular, inflammation and other disorders. A piperazino functionality as the tertiary pharmacophore remarkably improved the drug-like profile of the 1,3-disubstituted urea sEH inhibitors. However, the potency was more dependent on the overall best balance of the hydrophilicity and lipophilicity. Based on the sEH-inhibitor complex structure, further structural optimization on the piperazino-containing 1,3-disubstituted urea scaffold was conducted for an improved potency. The 1-adamantylacetamide and para-phenylcarbonyl group were identified to be an optimal primary pharmacophore and secondary pharmacophore motif, respectively, generating sub-nanomolar sEH inhibitors with favorable water solubility.

Original languageEnglish (US)
Pages (from-to)379-384
Number of pages6
JournalMedChemComm
Volume3
Issue number3
DOIs
StatePublished - Mar 2012

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Epoxide Hydrolases
Urea
Structural optimization
Hydrophilicity
Hydrophobic and Hydrophilic Interactions
Scaffolds
Solubility
Inflammation
Water
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Structure-based optimization of the piperazino-containing 1,3 -disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase. / Huang, Shao Xu; Cao, Bin; Morisseau, Christophe; Jin, Yi; Hammock, Bruce D.; Long, Ya Qiu.

In: MedChemComm, Vol. 3, No. 3, 03.2012, p. 379-384.

Research output: Contribution to journalArticle

Huang, Shao Xu ; Cao, Bin ; Morisseau, Christophe ; Jin, Yi ; Hammock, Bruce D. ; Long, Ya Qiu. / Structure-based optimization of the piperazino-containing 1,3 -disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase. In: MedChemComm. 2012 ; Vol. 3, No. 3. pp. 379-384.
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