PMID- 16784862
OWN - NLM
STAT- MEDLINE
DCOM- 20061106
LR  - 20231103
IS  - 0968-0896 (Print)
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 14
IP  - 19
DP  - 2006 Oct 1
TI  - The 5-substituted piperazine as a novel secondary pharmacophore greatly improving 
      the physical properties of urea-based inhibitors of soluble epoxide hydrolase.
PG  - 6586-92
AB  - 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 microM 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.
FAU - Li, Hui-Yuan
AU  - Li HY
AD  - State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 
      Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 
      Zuchongzhi Road, Shanghai 201203, China.
FAU - Jin, Yi
AU  - Jin Y
FAU - Morisseau, Christophe
AU  - Morisseau C
FAU - Hammock, Bruce D
AU  - Hammock BD
FAU - Long, Ya-Qiu
AU  - Long YQ
LA  - eng
GR  - R37 ES002710/ES/NIEHS NIH HHS/United States
GR  - R37 ES02710/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060619
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indicators and Reagents)
RN  - 0 (Piperazines)
RN  - 8W8T17847W (Urea)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Chemical Phenomena
MH  - Chemistry, Physical
MH  - Enzyme Inhibitors/*chemical synthesis/chemistry/*pharmacology
MH  - Epoxide Hydrolases/*antagonists & inhibitors
MH  - Humans
MH  - Indicators and Reagents
MH  - Magnetic Resonance Spectroscopy
MH  - Piperazines/*chemical synthesis/chemistry/*pharmacology
MH  - Spectrometry, Mass, Electrospray Ionization
MH  - Structure-Activity Relationship
MH  - Urea/*chemistry
PMC - PMC2040075
MID - NIHMS21264
EDAT- 2006/06/21 09:00
MHDA- 2006/11/07 09:00
PMCR- 2007/10/22
CRDT- 2006/06/21 09:00
PHST- 2006/04/19 00:00 [received]
PHST- 2006/06/02 00:00 [revised]
PHST- 2006/06/03 00:00 [accepted]
PHST- 2006/06/21 09:00 [pubmed]
PHST- 2006/11/07 09:00 [medline]
PHST- 2006/06/21 09:00 [entrez]
PHST- 2007/10/22 00:00 [pmc-release]
AID - S0968-0896(06)00459-7 [pii]
AID - 10.1016/j.bmc.2006.06.005 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2006 Oct 1;14(19):6586-92. doi: 10.1016/j.bmc.2006.06.005. Epub 
      2006 Jun 19.