Abstract
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
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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Cell Line
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Computer Simulation
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Humans
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Hydrocarbons, Fluorinated / chemistry
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Hydrocarbons, Fluorinated / pharmacology
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Hydrogen Bonding
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Liver X Receptors
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Mice
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Microsomes, Liver / metabolism
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Orphan Nuclear Receptors / agonists*
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Orphan Nuclear Receptors / metabolism
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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacology
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Sulfones / chemical synthesis
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Sulfones / chemistry*
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Sulfones / pharmacology
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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Hydrocarbons, Fluorinated
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Liver X Receptors
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Orphan Nuclear Receptors
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Quinolines
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Sulfonamides
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Sulfones
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T0901317