Abstract
A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRbeta and LXRalpha, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.
MeSH terms
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Animals
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Apolipoproteins E / genetics
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Atherosclerosis / genetics
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control*
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CHO Cells
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / pharmacology
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Chromatography, High Pressure Liquid
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / agonists*
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DNA-Binding Proteins / genetics
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Humans
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Indicators and Reagents
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Liver X Receptors
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Orphan Nuclear Receptors
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Phenylacetates / chemical synthesis*
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Phenylacetates / pharmacology*
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Quinolines / chemical synthesis*
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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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Recombinant Proteins / metabolism
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Solvents
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
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Transcriptional Activation / genetics
Substances
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Apolipoproteins E
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Carboxylic Acids
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DNA-Binding Proteins
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Indicators and Reagents
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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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Recombinant Proteins
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Solvents
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phenylacetic acid