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J. Lipid Res.
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A more recent version of this article appeared on December 1, 2009

Papers In Press, published online ahead of print March 24, 2009
J. Lipid Res., doi:10.1194/jlr.M900037-JLR200
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Submitted on January 29, 2009
Revised on March 13, 2009
Accepted on March 23, 2009

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

Elaine M. Quinet, Michael D. Basso, Anita R. Halpern, David W. Yates, Robert J. Sheffan, Valerie Clerin, Christine Resmini, James C. Keith, Thomas J. Berrodin, Irene Feingold, Wenyan Zhong, Helen B. Hartman, Mark J. Evans, Stephen J. Gardell, Elizabeth DiBlasio-Smith, William M. Mounts, Edward R. LaVallie, Jay Wrobel, Ponnal Nambi, and George P. Vlasuk

Cardiovascular and Metabolic Diseases, Wyeth, Cambridge, MA 02140

Corresponding Author: gvlasuk{at}wyeth.com

Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism and absorption. WAY-252623 (LXR-623), is a highly selective and orally bioavailable synthetic modulator of LXR, that demonstrated efficacy for reducing lesion progression in the murine LDLR-/- atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. In non-human primates with normal lipid levels, WAY-252623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time and dose dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. Statistically significant decreases in LDLc noted as early as 7d reached a maximum by 28d and exceeded reductions observed for simvastatin alone (20 mg/kg). Transient increases in circulating triglycerides and liver enzymes reverted to baseline levels over the course of the study. Complementary microarray analysis of duodenum and liver gene expression revealed differential activation of LXR target genes and suggests no direct activation of hepatic lipogenesis. WAY-252623, displays a unique and favorable pharmacological profile suggesting synthetic LXR ligands with these characteristics may be suitable for evaluation in patients with atherosclerotic dyslipidemia


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F. Briand, M. Treguier, A. Andre, D. Grillot, M. Issandou, K. Ouguerram, and T. Sulpice
Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model
J. Lipid Res., April 1, 2010; 51(4): 763 - 770.
[Abstract] [Full Text] [PDF]


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