TY - JOUR T1 - Novel Peroxisome Proliferator-Activated Receptor α Agonists Lower Low-Density Lipoprotein and Triglycerides, Raise High-Density Lipoprotein, and Synergistically Increase Cholesterol Excretion with a Liver X Receptor Agonist JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 716 LP - 726 DO - 10.1124/jpet.108.143271 VL - 327 IS - 3 AU - Ranjan Mukherjee AU - Kenneth T. Locke AU - Bowman Miao AU - Daniel Meyers AU - Hossain Monshizadegan AU - Rongan Zhang AU - Debra Search AU - Denise Grimm AU - Michael Flynn AU - Kevin M. O'Malley AU - Litao Zhang AU - Jun Li AU - Yan Shi AU - Lawrence J. Kennedy AU - Michael Blanar AU - Peter T. Cheng AU - Joseph Tino AU - Rai Ajit Srivastava Y1 - 2008/12/01 UR - http://jpet.aspetjournals.org/content/327/3/716.abstract N2 - The first generation peroxisome proliferator-activated receptor (PPAR) α agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARα agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARα-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 PPARα than human PPARα; therefore, they were tested in PPARα-humanized mice that do not express murine PPARα but express human PPARα 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 PPARα in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARα agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist. The American Society for Pharmacology and Experimental Therapeutics ER -