Activation of peroxisome proliferator-activated receptor alpha by substituted urea-derived soluble epoxide hydrolase inhibitors

Soluble Epoxide Hydrolase (sEH) plays a major role in regulating vascular epoxyeicosatrienoic acid metabolism and function, and substituted urea derivatives that inhibit sEH activity reduce blood pressure in hypertensive rats. We found that substituted urea derivatives containing a dodecanoic acid group, besides effectively inhibiting sEH, increased Peroxisome Proliferator-activated Receptor (PPAR) alpha activity. In PPARalpha transfected COS-7 cells, treatment with 10 microM N-cyclohexyl-N'-dodecanoic acid urea (CUDA) or N-adamantanyl-N'-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPARalpha activation. Neither CUDA nor AUDA activated PPARdelta or PPARgamma directly, indicating selectivity for PPARalpha. CUDA did not alter PPARalpha protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPARalpha, suggesting that it functions as a PPARalpha ligand. CUDA and AUDA were metabolized to chain-shortened beta-oxidation products, a process that reduced their potency as sEH inhibitors and their ability to bind and activate PPARalpha. N,N'-Dicylclohexylurea and N-cyclohexyl-N'-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPARalpha. In HepG2 cells, CUDA increased the expression of the PPARalpha-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPARalpha in addition to potently inhibiting sEH. Further development of these compounds could lead to a class of agents with hypotensive and lipid-lowering properties that may be valuable for the prevention and treatment of Cardiovascular Disease.