RT Journal Article SR Electronic T1 Identification of a Novel Selective Peroxisome Proliferator-Activated Receptor α Agonist, 2-Methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic Acid (LY518674), That Produces Marked Changes in Serum Lipids and Apolipoprotein A-1 Expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 763 OP 768 DO 10.1124/mol.105.010991 VO 68 IS 3 A1 Jai Pal Singh A1 Raymond Kauffman A1 William Bensch A1 Guoming Wang A1 Pam McClelland A1 James Bean A1 Chahrzad Montrose A1 Nathan Mantlo A1 Asavari Wagle YR 2005 UL http://molpharm.aspetjournals.org/content/68/3/763.abstract AB Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD. In this study, we have identified a potent (IC50 ∼24 nM) and selective peroxisome proliferator-activated receptor α (PPARα) agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674). In human apolipoprotein A-1 (apoA-1) transgenic mice, LY518674 produced a dose-dependent increase in serum HDL-c, resulting in 208 ± 15% elevation at optimum dose. A new synthesis of apoA-1 contributed to the increase in HDL-c. LY518674 increased apoA-1 mRNA levels in liver. Moreover, liver slices from animals treated with LY518674 secreted 3- to 6-fold more apoA-1 than control liver slices. In cultured hepatocytes, LY518674 produced 50% higher apoA-1 secretion, which was associated with increase in radiolabeled methionine incorporation in apoA-1. Thus, LY518674 is a potent and selective PPARα agonist that produced a much greater increase in serum HDL-c than the known fibrate drugs. The increase in HDL-c was associated with de novo synthesis of apoA-1.