Submitted to: American Society of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/11/2005
Publication Date: 1/1/2006
Citation: Davis, B.B., Morisseau, C., Pedersen, T., Newman, J.W., Hammock, B.D., Weiss, R.H. Attenuation of vascular smooth muscle cell proliferation by 1-cyclohexyl-3-dodecyl urea is independent of soluble epoxide hydrolase inhibition.. American Society of Pharmacology and Experimental Therapeutics. 2006: Vol.316, No.2:815-821. Interpretive Summary: The pharmacological properties of soluble epoxide hydrolase (sEH) inhibitors are being investigated for the treatment of hypertension, atherosclerosis, and inflammatory diseases. However, the pharmacological targets of these potential drugs have not been fully explored. This study found that one such sEH inhibitor, 1-cyclohexyl-3-dodecyl urea (CDU), inhibited the growth of multiple vascular cell types independent of an effect on the sEH, while other equally potent inhibitors and the endogenous epoxy fatty acid substrates of the target enzyme did not possess these properties. This study suggests that greasy cyclohexyl-ureas may have useful anti-proliferative properties, and caution against interpretation of biological effects when only found using micromolar concentrations of poorly characterized pharmacological agents.
Technical Abstract: Epoxyeicosatrienoic acid(s) (EET) have variable hemodynamic, anti-inflammatory, and growth regulatory effects, and inhibitors of their regulatory enzyme, soluble epoxide hydrolase (sEH), can mimic these effects. For this reason, sEH inhibitors are being studied as potential pharmaceuticals for the treatment of hypertension, atherosclerosis, and inflammatory diseases. We now show that a highly selective urea-based sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) attenuates human aortic vascular smooth muscle (HVSM) cell proliferation independently of any effect on sEH. CDU also inhibits endothelial cells when stimulated with basic fibroblast growth factor or serum. In addition, we demonstrate that EET, as well as several newer generation sEH inhibitors and a urea-based weak sEH inhibitor, do not affect proliferation in HVSM cells. Structure-activity relationships demonstrate that the addition of an acid group to the dodecyl carbon chain, changing the cyclohexyl group to an adamantyl group, and shortening the carbon chain to two carbons all abolish the antiproliferative effect. Our finding that a highly selective urea-based inhibitor of sEH can alter biology independently of its putative target enzyme suggests that there may be other useful properties of this class of compounds unrelated to their influence on epoxyeicosanoids. In addition, our results show that caution should be used when attempting to infer conclusions of EET biology based solely on the effects these inhibitors in tissue culture models, especially when used at micromolar concentrations.