Abstract
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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143271.
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ABBREVIATIONS: LDLc, low-density lipoprotein cholesterol; HDLc, high-density lipoprotein-cholesterol; CAD, coronary artery disease; DAIS, Diabetes Atherosclerosis Intervention Study; PPAR, peroxisome proliferator-activated receptor; LBD, ligand binding domain; Apo, apolipoprotein; LXR, liver X receptor; HEK, human embryonic kidney; FPLC, fast-protein liquid chromatography; PCR, polymerase chain reaction; VLDL, very low density lipoprotein; LPL, lipoprotein lipase; PDK4, pyruvate dehydrogenase kinase 4; HD, hydratase (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase).
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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↵1 Current affiliation: Diabetes Drug Discovery, Bristol-Myers Squibb, Pennington, New Jersey.
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↵2 Current affiliation: Global Research and Development Sourcing, Bristol-Myers Squibb, Pennington, New Jersey.
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↵3 Current affiliation: Immunology Chemistry, Bristol-Myers Squibb, Princeton, New Jersey.
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↵4 Current affiliation: Piramal Life Sciences, Mumbai, India.
- Received July 8, 2008.
- Accepted September 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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