Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide hydrolase inhibitors in murine models

Jun Yan Liu, Yan Ping Lin, Hong Qiu, Christophe Morisseau, Tristan E. Rose, Sung Hee Hwang, Nipavan Chiamvimonvat, Bruce D. Hammock

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Soluble epoxide hydrolase inhibitors (sEHIs) are anti-inflammatory, analgesic, anti-hypertensive, cardio- and renal-protective in multiple animal models. However, the earlier adamantyl-containing urea-based inhibitors are rapidly metabolized. Therefore, new potent inhibitors with the adamantyl group replaced by a substituted phenyl group were synthesized to presumptively offer better pharmacokinetic (PK) properties. Here we describe the improved PK profile of these inhibitors and the anti-inflammatory effect of the most promising one in a murine model. The PK profiles of inhibitors were determined following p.o. administration and serial bleeding in mice. The anti-inflammatory effect of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), the most promising inhibitor among the five sEHIs tested, was investigated in a lipopolysaccharide (LPS)-challenged murine model. The earlier broadly-used adamantyl-containing sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]- benzoic acid (t-AUCB), was used for comparison. Compared with the earlier adamantyl-containing urea-based inhibitors, substituted phenyl-containing urea-based inhibitors afford more favorable PK properties, such as higher C maxs, larger AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. Moreover, oral administration of TPPU dramatically reversed the shifts caused by LPS-challenge in plasma levels of inflammatory cytokines, epoxides and corresponding diols, which is more potent than t-AUCB. The substituted phenyl-containing sEHIs are more metabolically stable than those with adamantyl group, resulting in more potent efficacy in vivo. This indicates a new strategy for development of sEHIs for further study toward clinical trials.

Original languageEnglish (US)
Pages (from-to)619-627
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Volume48
Issue number4-5
DOIs
StatePublished - Mar 12 2013

Keywords

  • Anti-inflammation
  • Bioavailability
  • Eicosanoids
  • Metabolic profiling
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

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