Abstract
A series of branched and unbranched anilinohexafluoroisopropanols related to the known sulfonamide T0901317 were prepared and evaluated as activators/modulators of both LXRalpha and LXRbeta. A structure-activity relationship was established and compounds with high potency on both the receptors were identified. Many compounds showed a tendency toward selectivity for LXRbeta versus LXRalpha. Several analogues were evaluated for effects on plasma lipoprotein levels in mice. A few of these significantly raised HDL-cholesterol levels in plasma but showed markedly different effects on liver triglyceride content, suggesting that this series may yield candidates with improved efficacy/safety profiles compared to existing molecules.
MeSH terms
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Aniline Compounds / chemical synthesis*
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Aniline Compounds / pharmacokinetics
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Aniline Compounds / pharmacology
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Animals
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Atherosclerosis / drug therapy
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Cholesterol, HDL / blood
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DNA-Binding Proteins / drug effects*
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Lipoproteins / blood
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Liver
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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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Orphan Nuclear Receptors
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Propanols / chemical synthesis
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Propanols / pharmacokinetics
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Propanols / pharmacology
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Receptors, Cytoplasmic and Nuclear / drug effects*
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Structure-Activity Relationship
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Transcriptional Activation / drug effects
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Triglycerides / blood
Substances
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Aniline Compounds
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Cholesterol, HDL
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DNA-Binding Proteins
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Lipoproteins
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Liver X Receptors
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Nr1h3 protein, mouse
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Orphan Nuclear Receptors
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Propanols
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Receptors, Cytoplasmic and Nuclear
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Triglycerides