Abstract
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Binding Sites
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Blood-Brain Barrier / metabolism*
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Cell Line
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Computer Simulation
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Humans
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Hydrogen Bonding
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Liver X Receptors
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Orphan Nuclear Receptors / agonists*
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Orphan Nuclear Receptors / metabolism
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Protein Binding
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Rats
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Structure-Activity Relationship
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / pharmacokinetics
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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Liver X Receptors
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NR1H3 protein, human
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Nr1h3 protein, rat
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Orphan Nuclear Receptors
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Quinolines
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Sulfones