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

Jai Pal Singh, Raymond Kauffman, William Bensch, Guoming Wang, Pam McClelland, James Bean, Chahrzad Montrose, Nathan Mantlo, Asavari Wagle

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)763-768
Number of pages6
JournalMolecular Pharmacology
Volume68
Issue number3
DOIs
StatePublished - Sep 2005
Externally publishedYes

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Lipid A
Peroxisome Proliferator-Activated Receptors
Apolipoprotein A-I
HDL Cholesterol
Serum
Coronary Artery Disease
Liver
Fibric Acids
propionic acid
Methionine
LDL Cholesterol
Transgenic Mice
Inhibitory Concentration 50
Hepatocytes
Messenger RNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Singh, Jai Pal; Kauffman, Raymond; Bensch, William; Wang, Guoming; McClelland, Pam; Bean, James; Montrose, Chahrzad; Mantlo, Nathan; Wagle, Asavari.

In: Molecular Pharmacology, Vol. 68, No. 3, 09.2005, p. 763-768.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Singh, Jai Pal

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