Abstract

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) α activity. In PPARα transfected COS-7 cells, treatment with 10 μM N-cyclohexyl-N′-dodecanoic acid urea (CUDA) or N-adamantanyl-N′-dodecanoic acid urea (AUDA) produced 6- and 3-fold increases, respectively, in PPARα activation. Neither CUDA nor AUDA activated PPARδ or PPARγ directly, indicating selectivity for PPARα. CUDA did not alter PPARα protein expression, and it competitively inhibited the binding of Wy-14643 (pirinixic acid) to the ligand binding domain of PPARα, suggesting that it functions as a PPARα ligand. CUDA and AUDA were metabolized to chain-shortened β-oxidation products, a process that reduced their potency as sEH inhibitors and their ability to bind and activate PPARα. N,N′-Dicylclohexylurea and N-cyclohexyl-N′-dodecylurea, sEH inhibitors that do not contain a carboxylic acid group, did not activate PPARα. In HepG2 cells, CUDA increased the expression of the PPARα-responsive gene carnitine palmitoyltransferase 1A. We conclude that CUDA and AUDA, by virtue of their carboxylic acid substitution, activate PPARα 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.