Novel peroxisome proliferator-activated receptor alpha agonists lower low-density lipoprotein and triglycerides, raise high-density lipoprotein, and synergistically increase cholesterol excretion with a liver X receptor agonist

J Pharmacol Exp Ther. 2008 Dec;327(3):716-26. doi: 10.1124/jpet.108.143271. Epub 2008 Sep 17.


The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.

MeSH terms

  • Animals
  • Cholesterol / metabolism*
  • DNA-Binding Proteins / agonists*
  • Drug Synergism
  • Humans
  • Lipoproteins, HDL / blood*
  • Lipoproteins, LDL / blood*
  • Liver / metabolism
  • Liver X Receptors
  • Mice
  • Mice, Transgenic
  • Orphan Nuclear Receptors
  • PPAR alpha / agonists*
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Transcriptional Activation / drug effects
  • Triglycerides / blood*


  • DNA-Binding Proteins
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • PPAR alpha
  • Receptors, Cytoplasmic and Nuclear
  • Triglycerides
  • Cholesterol