PMID- 26620151
OWN - NLM
STAT- MEDLINE
DCOM- 20170117
LR  - 20220129
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 81
IP  - 5
DP  - 2016 May
TI  - Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a 
      novel soluble epoxide hydrolase inhibitor.
PG  - 971-9
LID - 10.1111/bcp.12855 [doi]
AB  - AIMS: Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone 
      and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a 
      potent and selective sEH inhibitor that was tested in two phase I studies. 
      METHODS: Single escalating doses of GSK2256294 2-20 mg or placebo were 
      administered in a randomized crossover design to healthy male subjects or obese 
      smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days 
      to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme 
      inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also 
      administered to healthy younger males or healthy elderly males and females with 
      and without food. Data on safety, pharmacokinetics and biliary metabolites were 
      collected. RESULTS: GSK2256294 was well-tolerated with no serious adverse events 
      (AEs) attributable to the drug. The most frequent AEs were headache and contact 
      dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with 
      a half-life averaging 25-43 h. There was no significant effect of age, food or 
      gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was 
      dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] 
      -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. 
      There were no significant changes in serum VEGF or plasma fibrinogen. 
      CONCLUSIONS: GSK2256294 was well-tolerated and demonstrated sustained inhibition 
      of sEH enzyme activity. These data support further investigation in patients with 
      endothelial dysfunction or abnormal tissue repair, such as diabetes, wound 
      healing or COPD.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Lazaar, Aili L
AU  - Lazaar AL
AD  - GSK R&D, King of Prussia, Pennsylvania, USA.
FAU - Yang, Lucy
AU  - Yang L
AD  - Experimental Medicine & Immunotherapeutics, Department of Medicine, University of 
      Cambridge, and Cambridge Clinical Trials Unit, Cambridge.
FAU - Boardley, Rebecca L
AU  - Boardley RL
AD  - GSK R&D, Stevenage, Cambridge and Ware.
FAU - Goyal, Navin S
AU  - Goyal NS
AD  - GSK R&D, King of Prussia, Pennsylvania, USA.
FAU - Robertson, Jonathan
AU  - Robertson J
AD  - GSK R&D, Stevenage, Cambridge and Ware.
FAU - Baldwin, Sandra J
AU  - Baldwin SJ
AD  - GSK R&D, Stevenage, Cambridge and Ware.
FAU - Newby, David E
AU  - Newby DE
AD  - University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, 
      UK.
FAU - Wilkinson, Ian B
AU  - Wilkinson IB
AD  - Experimental Medicine & Immunotherapeutics, Department of Medicine, University of 
      Cambridge, and Cambridge Clinical Trials Unit, Cambridge.
FAU - Tal-Singer, Ruth
AU  - Tal-Singer R
AD  - GSK R&D, King of Prussia, Pennsylvania, USA.
FAU - Mayer, Ruth J
AU  - Mayer RJ
AD  - GSK R&D, King of Prussia, Pennsylvania, USA.
FAU - Cheriyan, Joseph
AU  - Cheriyan J
AD  - Experimental Medicine & Immunotherapeutics, Department of Medicine, University of 
      Cambridge, and Cambridge Clinical Trials Unit, Cambridge.
AD  - GSK R&D, Stevenage, Cambridge and Ware.
AD  - Cambridge University Hospitals NHS Foundation Trust, Cambridge and.
LA  - eng
SI  - ClinicalTrials.gov/NCT01762774
SI  - ClinicalTrials.gov/NCT02006537
GR  - 103782/WT_/Wellcome Trust/United Kingdom
GR  - FS/12/8/29377/BHF_/British Heart Foundation/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20160117
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Cyclohexylamines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 
      (N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide)
RN  - 0 (Triazines)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.3.2.10 (EPHX2 protein, human)
RN  - FC398RK06S (8,11,14-Eicosatrienoic Acid)
SB  - IM
MH  - 8,11,14-Eicosatrienoic Acid/*analogs & derivatives/metabolism
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Cohort Studies
MH  - Cross-Over Studies
MH  - Cyclohexylamines/adverse effects/pharmacokinetics/*pharmacology
MH  - Dermatitis, Contact/etiology
MH  - Double-Blind Method
MH  - Enzyme Inhibitors/adverse effects/pharmacokinetics/*pharmacology
MH  - Epoxide Hydrolases/*antagonists & inhibitors/metabolism
MH  - Female
MH  - Half-Life
MH  - Headache/chemically induced
MH  - Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Obesity/*drug therapy
MH  - Triazines/adverse effects/pharmacokinetics/*pharmacology
MH  - Young Adult
PMC - PMC4834590
OTO - NOTNLM
OT  - COPD
OT  - clinical pharmacology
OT  - clinical trial
OT  - smoking
OT  - soluble epoxide hydrolase
EDAT- 2015/12/02 06:00
MHDA- 2017/01/18 06:00
PMCR- 2017/05/01
CRDT- 2015/12/02 06:00
PHST- 2015/10/09 00:00 [received]
PHST- 2015/11/25 00:00 [revised]
PHST- 2015/11/26 00:00 [accepted]
PHST- 2015/12/02 06:00 [entrez]
PHST- 2015/12/02 06:00 [pubmed]
PHST- 2017/01/18 06:00 [medline]
PHST- 2017/05/01 00:00 [pmc-release]
AID - BCP12855 [pii]
AID - 10.1111/bcp.12855 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2016 May;81(5):971-9. doi: 10.1111/bcp.12855. Epub 2016 Jan 
      17.