Objective-Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. Methods and Results-Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1␣, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. Key Words: epoxyeicosatrienoic acids Ⅲ soluble epoxide hydrolase Ⅲ dyslipidemia Ⅲ atherosclerosis Ⅲ abdominal aorta aneurysm Ⅲ inflammatory markers A rachidonic acid can be metabolized by 3 major oxidative pathways: cyclooxygenase (COX) forming prostaglandins; lipoxygenase (LOX) forming hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and cytochrome P-450 monooxygenase forming epoxides and HETEs. 1 The COX and LOX pathways have been extensively studied, and their eicosanoid products have been shown to play important roles in a variety of biological processes such as inflammation, cell proliferation, and intracellular signaling. In contrast, less is known about the "third pathway" of arachidonic acid metabolism. Recently, epoxyeicosatrienoic acids (EETs), the cytochrome P450 metabolites of arachidonic acid, have received increasing attention for multiple beneficial biological functions, including vasodilation, antiinflammation, and inhibition of proliferation and migration of vascular smooth muscle cells. 1,2 Based on these properties, it has been postulated that EETs may exert therapeutic benefits in inflammatory vascular diseases, such as atherosclerosis. 2,3 Soluble epoxide hydrolase (s-EH) converts EETs into their corresponding dihydroxyeicosatrienoic acids (DHETs), which are generally thought to have reduced biological activity relative to EETs, and hydration of the EETs by s-EH is a dominant mechanism whereby their activity can be reduced. 4 Thus, inhibition of s-EH could be a promising therapeutic target for amplifying the beneficial effects of EETs. 4 Indeed, s-EH inhibitors have been demonstrated to lower blood pressure in hypertension, 5,6 decrease hypertension-induced renal damage 7 and cerebral ischemia injury, 8 attenuate vascular smooth muscle cell proliferation, 9 and reduce tissue...

AR9281, a potent and selective inhibitor of soluble epoxide hydrolase (s-EH), is in clinical development targeting hypertension and type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamics of AR9281 were evaluated in double-blind, randomized, placebo-controlled, ascending, single oral dose (10-1000 mg) and multiple dose (100-400 mg every 8 hours for 7 days) studies in healthy subjects. AR9281 was well tolerated, and no dose-related adverse events were observed during either study. The drug was rapidly absorbed with a mean terminal half-life ranging from 3 to 5 hours. The area under the plasma concentration-time curve increased in an approximately dose-proportional manner up to the 500-mg dose and exhibited a greater than dose linearity at higher doses. AR9281 directly and dose-dependently inhibited blood s-EH activity with 90% inhibition or greater over an 8-hour period at the 250-mg dose and over a 12-hour period at the 500-mg dose. Multiple doses of AR9281 ranging from 100 to 400 mg every 8 hours resulted in a sustained inhibition of s-EH activity at 90% or greater during the trough. The current studies provide proof of safety and target inhibition of AR9281 in healthy subjects. AR9281 pharmacokinetic and pharmacodynamic characteristics support a twice-daily or thrice-daily dosing regimen in patients.

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1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin-resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

have reported chemical shifts and coupling constants for cis and trans dihydrodiol diacetates at K-regions of several polycyclic hydrocarbons. The basis of the assignments given were not provided, and, in some instances, are divergent with the concepts presented here.(38) P. M. DansetteAbstract: A simple and practical route to poly(viny1amine hydrochloride) has been developed. Ethylidene bisacetamide was prepared by condensing (sulfuric acid catalyst) acetaldehyde with 2 equiv of acetamide. After neutralization of the acid with calcium carbonate, the intermediate was directly pyrolyzed (175-195 "C) in the presence of a surface catalyst (Celite) to Nvinylacetamide. Polymerization of the unpurified product, followed by acid hydrolysis of the resulting poly(N-vinylacetamide), afforded poly(viny1amine hydrochloride) in an overall yield of greater than 80% from acetaldehyde. A series of watersoluble, polymeric azo dyes was prepared from poly(viny1amine hydrochloride) by a sequence of reactions which consisted of (1 ) a Schotten-Baumann reaction of the polymer with p-acetamidobenzenesulfonyl chloride in aqueous tetrahydrofuran; (2) hydrolysis of the p-acetamido function in hydrochloric acid to afford a polymeric sulfanilamide; (3) diazotization: (4) reaction of the resulting diazonium salt with sulfonated coupling agents. Some of the physical properties of these polymeric dyes are briefly discussed.