Abstract
We have identified a novel liver X receptor (LXR) agonist (2) that activates the LXRbeta subtype with selectivity over LXRalpha. LXRbeta selectivity was confirmed using macrophages derived from LXR mutant mice. Despite its selectivity and modest potency, the compound can induce APO-AI-dependent cholesterol efflux from macrophages with full efficacy. Our results indicate that it is possible to achieve significant LXRbeta selectivity in a small molecule while maintaining functional LXR activity.
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / biosynthesis
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Animals
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Apolipoprotein A-I / pharmacology
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Cell Line
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Cholesterol / metabolism
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Crystallography, X-Ray
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DNA-Binding Proteins / agonists*
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DNA-Binding Proteins / genetics
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Liver X Receptors
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Knockout
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis*
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology
Substances
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5-(4-chlorophenyl)-3-(2,4,6-trifluorophenyl)-2,3-dihydro-2-(2,3-dimethoxyphenyl)-1,3,4-thiadiazole
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters
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Apolipoprotein A-I
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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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Thiadiazoles
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Cholesterol