PMID- 17616115
OWN - NLM
STAT- MEDLINE
DCOM- 20071109
LR  - 20220310
IS  - 0022-2623 (Print)
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 50
IP  - 16
DP  - 2007 Aug 9
TI  - Orally bioavailable potent soluble epoxide hydrolase inhibitors.
PG  - 3825-40
AB  - A series of N,N'-disubstituted ureas having a conformationally restricted cis- or 
      trans-1,4-cyclohexane alpha to the urea were prepared and tested as soluble 
      epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar 
      to picomolar activities against recombinant human sEH. Both isomers showed 
      similar potencies, but the trans isomers were more metabolically stable in human 
      hepatic microsomes. Furthermore, these new potent inhibitors show a greater 
      metabolic stability in vivo than previously described sEH inhibitors. We 
      demonstrated that trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 
      13g (t-AUCB, IC50 = 1.3 +/- 0.05 nM) had excellent oral bioavailability (98%, n = 
      2) and blood area under the curve in dogs and was effective in vivo to treat 
      hypotension in lipopolysaccharide challenged murine models.
FAU - Hwang, Sung Hee
AU  - Hwang SH
AD  - Department of Entomology and UCD Cancer Center, University of California-Davis, 
      One Shields Avenue, Davis, CA 95616-8584, USA.
FAU - Tsai, Hsing-Ju
AU  - Tsai HJ
FAU - Liu, Jun-Yan
AU  - Liu JY
FAU - Morisseau, Christophe
AU  - Morisseau C
FAU - Hammock, Bruce D
AU  - Hammock BD
LA  - eng
GR  - R37 ES002710-27/ES/NIEHS NIH HHS/United States
GR  - ES 02710/ES/NIEHS NIH HHS/United States
GR  - P42 ES 04699/ES/NIEHS NIH HHS/United States
GR  - R01 ES002710/ES/NIEHS NIH HHS/United States
GR  - P30 ES005707/ES/NIEHS NIH HHS/United States
GR  - P42 ES004699-21/ES/NIEHS NIH HHS/United States
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - P30 ES 05707/ES/NIEHS NIH HHS/United States
GR  - P30 ES005707-119017/ES/NIEHS NIH HHS/United States
GR  - R37 ES002710/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070706
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid)
RN  - 0 (Benzoates)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Recombinant Proteins)
RN  - 8W8T17847W (Urea)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - PJY633525U (Adamantane)
SB  - IM
MH  - Adamantane/*analogs & derivatives/*chemical synthesis/pharmacokinetics
MH  - Administration, Oral
MH  - Animals
MH  - Benzoates/*chemical synthesis/pharmacokinetics
MH  - Biological Availability
MH  - Cats
MH  - Cricetinae
MH  - Dogs
MH  - Epoxide Hydrolases/*antagonists & inhibitors/chemistry
MH  - Humans
MH  - Hypotension/chemically induced/drug therapy
MH  - In Vitro Techniques
MH  - Lipopolysaccharides
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microsomes, Liver/metabolism
MH  - Models, Molecular
MH  - Rats
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry
MH  - Solubility
MH  - Species Specificity
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Urea/*analogs & derivatives/chemical synthesis/pharmacokinetics
PMC - PMC2596069
MID - NIHMS69355
EDAT- 2007/07/10 09:00
MHDA- 2007/11/10 09:00
PMCR- 2008/12/04
CRDT- 2007/07/10 09:00
PHST- 2007/07/10 09:00 [pubmed]
PHST- 2007/11/10 09:00 [medline]
PHST- 2007/07/10 09:00 [entrez]
PHST- 2008/12/04 00:00 [pmc-release]
AID - 10.1021/jm070270t [doi]
PST - ppublish
SO  - J Med Chem. 2007 Aug 9;50(16):3825-40. doi: 10.1021/jm070270t. Epub 2007 Jul 6.