title: In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor.
abstract: Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.
authors: Stress & Repair Discovery Performance Unit, Respiratory Therapeutic Area, GlaxoSmithKline, King of Prussia, PA 19406, USA. patty.podolin@gsk.com
authors: Patricia L
authors: PL
authors: Podolin
authors: Brian J
authors: BJ
authors: Bolognese
authors: Joseph F
authors: JF
authors: Foley
authors: Edward
authors: E
authors: Long
authors: Brian
authors: B
authors: Peck
authors: Sandra
authors: S
authors: Umbrecht
authors: Xiaojun
authors: X
authors: Zhang
authors: Penny
authors: P
authors: Zhu
authors: Benjamin
authors: B
authors: Schwartz
authors: Wensheng
authors: W
authors: Xie
authors: Chad
authors: C
authors: Quinn
authors: Hongwei
authors: H
authors: Qi
authors: Sharon
authors: S
authors: Sweitzer
authors: Stephanie
authors: S
authors: Chen
authors: Marc
authors: M
authors: Galop
authors: Yun
authors: Y
authors: Ding
authors: Svetlana L
authors: SL
authors: Belyanskaya
authors: David I
authors: DI
authors: Israel
authors: Barry A
authors: BA
authors: Morgan
authors: David J
authors: DJ
authors: Behm
authors: Joseph P
authors: JP
authors: Marino
authors: Edit
authors: E
authors: Kurali
authors: Mary S
authors: MS
authors: Barnette
authors: Ruth J
authors: RJ
authors: Mayer
authors: Catherine L
authors: CL
authors: Booth-Genthe
authors: James F
authors: JF
authors: Callahan
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D003514:Cyclohexylamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D013229:Stearic Acids / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D014227:Triazines / Q000494:pharmacology*
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; C120038:9,10-dihydroxy-12-octadecenoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D054360:Chemokine CXCL1; D003514:Cyclohexylamines; D005098:Exotoxins; C584201:N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide; D013229:Stearic Acids; D014028:Tobacco Smoke Pollution; D014227:Triazines; C018579:leukotoxin; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid