Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties

Shao Xu Huang, Hui Yuan Li, Jun Yan Liu, Christophe Morisseau, Bruce D. Hammock, Ya Qiu Long

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation, and other disorders. However, the problems of limited water solubility, high melting point, and low metabolic stability complicated the development of 1,3-disubstituted urea-based sEH inhibitors. The current study explored the introduction of the substituted piperazino group as the tertiary pharmacophore, which resulted in substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors while retaining high potency. The SAR studies revealed that the meta- or para-substituted phenyl spacer and N4-acetyl or sulfonyl substituted piperazine were optimal structures for achieving high potency and good physical properties. The 1-(4-(4-(4-acetylpiperazin-1-yl)butoxy)phenyl)-3-adamantan-1-yl urea (29c) demonstrated excellent in vivo pharmacokinetic properties in mice: T 1/2 =14 h, Cmax = 84 nM, AUC = 40 200 nM·min, and IC50 = 7.0 nM against human sEH enzyme.

Original languageEnglish (US)
Pages (from-to)8376-8386
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number23
DOIs
StatePublished - Dec 9 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Incorporation of piperazino functionality into 1,3-disubstituted urea as the tertiary pharmacophore affording potent inhibitors of soluble epoxide hydrolase with improved pharmacokinetic properties'. Together they form a unique fingerprint.

  • Cite this