Safety and pharmacology of a soluble epoxide hydrolase inhibitor

Lazaar, Aili L.; Yang, Lucy; Robertson, Jonathan; Goyal, Navin; Boardley, Rebecca L.; Tal‐Singer, Ruth; Cheriyan, Joseph; Singh, Trisha; Wilkinson, Ian B.; Mayer, Ruth

doi:10.1183/13993003.congress-2015.pa2120

Cited by 2 publications

(12 citation statements)

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“…Data were collected on safety, PK, sEH enzyme inhibition and blood biomarkers. An experimental medicine study in cohorts 3 and 4, to provide early proof of mechanism of the potential biological effects of sEH inhibition on endothelial function using measurements of forearm blood flow, was also included, but reported separately . The trial received favourable ethical opinion from the London Bloomsbury Ethics Committee (12/LO/1832) as well as regulatory approval by the MHRA.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

Lazaar

Yang

Boardley

et al. 2016

Brit J Clinical Pharma

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126

116

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AIMSEndothelial-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. METHODSSingle 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. RESULTSGSK2256294 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.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

Lazaar

Yang

Boardley

et al. 2016

Brit J Clinical Pharma

Self Cite

126

116

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“…6 For this reason, thiourea 9, carbamate 11, and urea 13 were first synthesized in order to explore their relative potency as an sEHI and to select the more suitable pharmacophore for the novel polycyclic scaffold (Scheme 1). The three compounds were easily synthesized in low to moderate yields from known 9-methyl-5,6,8,9,10,11hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-amine 13 (II, R = CH 3 , X = CH 2 ) and 4-(trifluoromethyl)phenyl isothiocyanate, 8, p-tolyl chloroformate, 10, and 2,3,4trifluorophenyl isocyanate, 12, respectively (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…1-(9-Methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11dimethanobenzo [9]annulen-7-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (9). To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-amine hydrochloride (250 mg, 0.95 mmol) in DCM (2 mL), 1-isothiocyanato-4-(trifluoromethyl)benzene (193 mg, 0.95 mmol) and Et 3 N (287 mg, 2.84 mmol) were added. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum.…”

Section: Methodsmentioning

confidence: 99%

“…13 C NMR (100.5 MHz, CDCl 3 ): δ 32.2 (CH 3 , C9−CH 3 ), 33.9 (C, C9), 38.9 [CH 2 , C6( 12 4.1.1.2. p-Tolyl (9-Methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11dimethanobenzo [9]annulen-7-yl)carbamate (11). To a solution of 9-methyl-5,6,8,9,10,11-hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-amine hydrochloride (250 mg, 0.95 mmol) in DCM (2 mL), p-tolyl chloroformate (194 mg, 1.14 mmol) and Et 3 N (287 mg, 2.84 mmol) were added. The reaction mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum.…”

Section: Methodsmentioning

confidence: 99%

“…8 GSK2256294, developed for chronic obstructive pulmonary disease by GlaxoSmithKline, has entered clinical trials for obese smokers and other indications such as subarachnoidal hemorrhage or diabetic patients with insulin resistance. 9 More recently, taking the AR9281 failure into account, EicOsis has recently replaced the adamantyl moiety of AR9281 by an aromatic ring for its drug candidate EC5026, which has recently completed human phase 1a clinical trials for the treatment of neuropathic pain. 10 Using urea-based sEHIs with lipophilic units of very different sizes, we recently found that the pocket of the sEH can accommodate polycycles of a quite diverse volume and that the replacement of the adamantane moiety by larger polycyclic rings, such as the diamantane moiety, may be better than the replacement by smaller ones.…”

Section: Introductionmentioning

confidence: 99%

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From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis

et al. 2021

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The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

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Safety and pharmacology of a soluble epoxide hydrolase inhibitor

Cited by 2 publications

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Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor

From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis

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