Abstract
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
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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Anticholesteremic Agents / chemical synthesis*
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Anticholesteremic Agents / chemistry
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Anticholesteremic Agents / pharmacology
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Atherosclerosis / drug therapy*
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Binding Sites
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Biological Availability
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Cell Line
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Cholesterol / metabolism
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DNA-Binding Proteins / agonists*
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DNA-Binding Proteins / genetics
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Drug Stability
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Female
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Humans
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In Vitro Techniques
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Ligands
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Liver X Receptors
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Orphan Nuclear Receptors
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Phenylacetates / chemical synthesis*
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Phenylacetates / chemistry
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Phenylacetates / pharmacology
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Protein Structure, Tertiary
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / genetics
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Structure-Activity Relationship
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Transcriptional Activation
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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Anticholesteremic Agents
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DNA-Binding Proteins
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Ligands
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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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Phenylacetates
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Quinolines
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Receptors, Cytoplasmic and Nuclear
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Cholesterol
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phenylacetic acid