- Substituted adamantyl-urea inhibitors of the soluble epoxide hydrolase dilate mesenteric resistance vessels
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The epoxyeicosatrienoic acids (EETs) have been identified as endothelium-derived hyperpolarizing factors. Metabolism of the EETs to the dihydroxyeicosatrienoic acids is catalyzed by soluble epoxide hydrolase (sEH). Administration of urea-based sEH inhibitors provides protection from hypertension-induced renal injury at least in part by lowering blood pressure. Here, we investigated the hypothesis that a mechanism by which sEH inhibitors elicit their cardiovascular protective effects is via their action on the vasculature. Mesenteric resistance arteries were isolated from Sprague-Dawley rats, pressurized, and constricted with the thromboxane A2 agonist U46619 (9,11-dideoxy-11,9-epoxymethano-prostaglandin F2α). Mesenteric arteries were then incubated with increasing concentrations of the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). AUDA resulted in a concentration-dependent relaxation of mesenteric arteries, with 10 μM resulting in a 48 ± 7% relaxation. Chain-shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 μM, the sEH inhibitors 1-cyclohexyl-3-dodecylurea, 12-(3-cyclohexylureido) dodecanoic acid, and 950 [adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea] were significantly less active, resulting in a 25 ± 8%, 10 ± 9%, and -8 ± 3% relaxation, respectively. Treatment of mesenteric arteries with tetraethylammonium, iberiotoxin, ouabain, or glibenclamide did not alter AUDA-induced relaxation. The AUDA-induced relaxation was completely inhibited when constricted with KCl. In separate experiments, denuding mesenteric resistance vessels did not alter AUDA-induced relaxation. Taken together, these data demonstrate that adamantyl-urea inhibitors have unique dilator actions on vascular smooth muscle compared with other sEH inhibitors and that these dilator actions depend on the adamantyl group and carbon chain length. Copyright
- Olearczyk, Jeffrey J.,Field, Mary B.,Kim, In-Hae,Morisseau, Christophe,Hammock, Bruce D.,Imig, John D.
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- 4′-(2-(2-Ethoxyethoxy)ethoxy)biphenyl-4-carboxylic acid-a polar smectogen for amphipathic liquid crystals
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We describe a new calamitic smectogen and some of its esters with a three-block molecular architecture (polar oxyethylene chain, rigid biphenyl and non-polar aliphatic chain) which were characterised by a combination of optical, thermical, X-ray and computational techniques. The title compound is a valuable smectogenic building block for amphipathic functional organic materials.
- Montani, Rosana S.,Hegguilustoy, Claudia M.,Del Rosso, Pablo G.,Donnio, Bertrand,Guillon, Daniel,Garay, Raúl O.
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scheme or table
p. 5231 - 5234
(2009/12/06)
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- 1,3-Disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties
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Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.
- Kim, In-Hae,Tsai, Hsing-Ju,Nishi, Kosuke,Kasagami, Takeo,Morisseau, Christophe,Hammock, Bruce D.
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p. 5217 - 5226
(2008/03/13)
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- Design, Synthesis, and Structure-Activity Relationship Studies for a New Imidazole Series of J774 Macrophage Specific Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors
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Acyl-CoA:cholesterol acyltransferase (ACAT) is the primary enzyme involved in intracellular cholesterol esterification.Arterial wall infiltration by macrophages and subsequent uncontrolled esterification of cholesterol leading to foam cell formation is believed to be an important process which leads to the development of fatty streaks.Inhibitors of the ACAT enzyme may retard this atherogenic process.We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay.This paper will describe the design, synthesis, and structure-activity relationship for this very potent series of compounds.
- Maduskuie, Thomas P.,Wilde, Richard G.,Billheimer, Jeffrey T.,Cromley, Debra A.,Germain, Sandra,et al.
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p. 1067 - 1083
(2007/10/02)
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- MACROHETEROCYCLES. IX. SYNTHESIS AND SOME CHARACTERISTICS OF MACROCYCLIC AMIDIC ESTERS OF SUCCINIC AND DIGLYCOLIC ACIDS
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A series of dicarboxylic acids were obtained by acylation of 1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 3-oxa-1,5-pentanediol, 3,6-dioxa-1,8-octanediol, 3,6,9-trioxa-1,11-undecanediol, and glycolic, thioglycolic, and phenyllactic acids with succinic a
- Luk'yanenko, N. G.,Bogat-skii, A. V.,Shapkin, V. A.,Popkov, Yu. A.
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p. 944 - 950
(2007/10/02)
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