Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGFand fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg·kg −1 ·d −1 ) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ∼70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.

A series of N,N′-disubstituted ureas having a conformationally restricted cis-or trans-1,4-cyclohexane α 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, IC 50 = 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.

A series of 1,3-disubstituted ureas possessing a piperidyl moiety has been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of thirteen 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantyl-urea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax† and a 3300 fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000 fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawl threshold using the in vivo carrageenan induced inflammatory pain model.

Background and purpose: Early soluble epoxide hydrolase inhibitors (sEHIs) such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) are effective anti-hypertensive and anti-inflammatory agents in various animal models. However, their poor metabolic stability and limited water solubility make them difficult to use pharmacologically. Here we present the evaluation of four sEHIs for improved pharmacokinetic properties and the anti-inflammatory effects of one sEHI. Experimental approach: The pharmacokinetic profiles of inhibitors were determined following p.o. (oral) administration and serial bleeding in mice. Subsequently the pharmacokinetics of trans-4- [4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), the most promising inhibitor, was further studied following s.c. (subcutaneous), i.v. (intravenous) injections and administration in drinking water. Finally, the anti-inflammatory effect of t-AUCB was evaluated by using a lipopolysaccharide (LPS)-treated murine model. Key results: Better pharmacokinetic parameters (higher Cmax, longer t1/2 and greater AUC) were obtained from the tested inhibitors, compared with AUDA. Oral bioavailability of t-AUCB (0.1 mg·kg -1 ) was 68 Ϯ 22% (n = 4), and giving t-AUCB in drinking water is recommended as a feasible, effective and easy route of administration for chronic studies. Finally, t-AUCB (p.o.) reversed the decrease in plasma ratio of lipid epoxides to corresponding diols (a biomarker of soluble epoxide hydrolase inhibition) in lipopolysaccharide-treated mice. The in vivo potency of 1 mg·kg -1 of t-AUCB (p.o.) was better in this inflammatory model than that of 10 mg·kg -1 of AUDA-butyl ester (p.o) at 6 h after treatment. Conclusions and implications: t-AUCB is a potent sEHI with improved pharmacokinetic properties. This compound will be a useful tool for pharmacological research and a promising starting point for drug development. (2009) , cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid; t-AUCB, trans-AUCB; APAU, 1-(1-acetypiperidin-4-yl)-3-adamantanylurea; AUDA, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid; AUDA-BE, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester; BPAU, 1-(5-butoxypentyl)-3-adamantylurea; CMNPC, cyano(2-methoxynaphthalen-6-yl)methyl(3-phenyloxiran-2-yl)methyl carbonate; EET, epoxyeicosatrienoic acid; DHET, dihydroxyeicosatrieneoic acid; DHOME, dihydroxy octadecamonoeneoic acid; EpOME, epoxyoctadecamonoeneoic acid; HETE, hydroxyeicosatetraenoic acid; NF-kB, nuclear factor kappa B; LPS, lipopolysaccharide; PG, prostaglandin; PK, pharmacokinetic; sEH, soluble epoxide hydrolase; sEHI, sEH inhibitor; TOIC50, time of blood concentration over IC50; TPAU, 1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea British Journal of Pharmacology