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Identification of a Novel Selective Peroxisome Proliferator-Activated Receptor 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

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

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 (PPAR) 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 PPAR 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.

Address correspondence to: Dr. Jai Pal Singh, Lilly Research Laboratories, DC:0520, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: singh_jaipal{at}lilly.com

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