Abstract
A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / metabolism
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Administration, Oral
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Amines / chemical synthesis*
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Amines / chemistry
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Amines / pharmacology
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Animals
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Biological Availability
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Cell-Free System
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Cholesterol / metabolism
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Cholesterol, HDL / blood
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DNA-Binding Proteins
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Genes, Reporter
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Humans
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Intestine, Small / metabolism
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Liver X Receptors
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Retinoic Acid / agonists*
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Receptors, Thyroid Hormone / agonists*
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Structure-Activity Relationship
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Up-Regulation
Substances
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ABCA1 protein, human
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters
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Amines
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Cholesterol, HDL
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DNA-Binding Proteins
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Liver X Receptors
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NR1H3 protein, human
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Nr1h3 protein, mouse
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Cholesterol