The 5-substituted piperazine as a novel secondary pharmacophore greatly improving the physical properties of urea-based inhibitors of soluble epoxide hydrolase

Hui Yuan Li, Yi Jin, Christophe Morisseau, Bruce D. Hammock, Ya Qiu Long

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertention and inflammation. The problems of limited water solubility and high melting points commonly displayed by the active 1,3-disubstituted ureas prevent the further development of potent urea-based sEH inhibitors. Therefore, a new class of potent inhibitors of sEH were designed and synthesized by the introduction of a polar constrained piperazino group in the right side of adasmantyl urea to increase the water solubility. A facile and general synthesis was established to prepare a series of 1-adamantan-1-yl-3-(2-piperazin-2-yl-ethyl)-ureas (1a-d) with various 5-substitutions on the 2-piperazino ring, which will advance the SAR study by the efficient making of structurally diverse analogs. The effect of the 5-substitution on the activity and the water solubility was examined. The best potency was exhibited by the 5-benzyl-substituted-piperazine-containing urea with an IC50 value of 1.37 μM against human sEH and good water solubility (S = 7.46 mg/mL) and low melting point, in which the 5-substituted piperazine serves as a favorable secondary pharmacophore and a water-solubility enhancing group. Our present work provides a promising new template for the design of orally available therapeutic agents for the disorders that can be addressed by changing the in vivo concentration of the chemical mediators that contain an epoxide.

Original languageEnglish (US)
Pages (from-to)6586-6592
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number19
DOIs
StatePublished - Oct 1 2006

Keywords

  • 1-adamantanyl-urea-based inhibitors
  • Chiral pool synthesis
  • Hypertension
  • Piperazine
  • Secondary pharmacophore
  • Soluble epoxide hydrolase
  • Vascular inflammation
  • Water solubility

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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