Activation of peroxisome proliferator-activated receptor α 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 PPAR alpha transfected COS-7 cells, treatment with 10 mu M N-cyclohexyl-N'-dode-canoic acid urea (CUDA) or N-adamantanyl-N'-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPAR alpha activation. Neither CUDA nor AUDA activated PPAR delta or PPAR gamma directly, indicating selectivity for PPAR alpha. CUDA did not alter PPAR alpha protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPAR alpha, suggesting that it functions as a PPAR alpha 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 PPAR alpha. N, N'-Dicylclohexylurea and N-cyclohexyl- N'-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPAR alpha. In HepG2 cells, CUDA increased the expression of the PPAR alpha-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPAR alpha 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.