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Compounds as liver X receptor modifier

A compound and drug technology, applied in the field of compounds as liver X receptor modulators, can solve problems such as unreported regulation of LXR

Active Publication Date: 2009-09-30
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(Phytochemistry 58 (2001) 357-362, Journal of Experimental Therapeutics and Oncology 3: 283-288, 2003), but its LXR regulation has not been reported

Method used

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  • Compounds as liver X receptor modifier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1, assay of cell transcription activity

[0054] Transcription assays are used to evaluate the ability of compounds of the invention to modulate LXR transcriptional activity. Briefly, an expression vector for a chimeric protein was co-transfected into mammalian cells by transient transfection together with a reporter gene vector in which the luciferase gene was under the control of the binding site of the regulatory protein GAL4 in yeast. Contains the DNA binding domain (DBD) of Gal4 fused to the ligand binding domain (LBD) of human LXRa or LXRβ. In the presence of LXR modulators, LXR transcriptional activity is altered, which can be monitored by changes in luciferase levels. If transfected cells are exposed to LXR agonists, LXR-dependent transcriptional activity increases and luciferase levels rise.

[0055] 48 hours before the start of this experiment, HEK293 cells (1×10 7 ) inoculated at 175cm 2 In the culture flask, the medium is DMEM medium with 10% ...

Embodiment 2

[0060] Example 2, LXR-FP (fluorescence polarization)-activator co-recruitment experiment

[0061] FP assays are used to evaluate the ability of compounds of the invention to bind directly to the LXR ligand binding domain (LBD) and promote the recruitment of proteins (eg, coactivators) that potentiate LXR transcriptional activity. This cell-free in vitro assay uses a recombinant fusion protein consisting of LXR-LBD and a purified tag such as His-tag, as well as a synthetic fluorescein isothiocyanate (FITC)-tagged peptide derived from a coactivator Nuclear receptor interacting binding domains of proteins such as steroid receptor coactivator 1 (SRC-1). In the presence of LXR agonists, fluorescently labeled coactivator peptides are recruited to the LXR-LBD, so that low fluorescence polarization values ​​become high fluorescence polarization values, and the magnitude of the polarized fluorescence values ​​gives the definition of coactivator peptide recruitment. Indication of poten...

Embodiment 3

[0067] Example 3. Experiment of resveratrol oligomers inhibiting foaming of macrophages

[0068] The foaming inhibitory effect of macrophages was studied on the compound of the present invention.

[0069] Trypsinize the cultured macrophages and count as the cell density should be approximately 3 x 10 5 per ml, add 1 ml per well to a 24-well culture plate. The cells were divided into blank control group, foam cell group and sample addition group. In the blank control group, only serum-free culture medium was added, in the foam cell group, ox-LDL was added to a final concentration of 50 μg / ml in each well, in the sample adding group, on the basis of the foam group, the sample to be tested was added, mixed evenly and placed in 37 ℃ containing 5% CO, cultured in an incubator for 48 hours and stained with Oil Red 0, which can stain neutral lipids.

[0070] After 48 hours of incubation with OX-LDL-treated macrophages, the results were as follows figure 1 As shown, the cells in t...

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Abstract

The invention discloses compounds as a liver X receptor modifier, and in particular relates to resveratrol tetramer compounds. The compounds can be used for preparing a medicament for treating or preventing diseases or symptoms related to the activity of a liver X receptor (LXR), and the medicament can prevent and treat neurodegenerative disease, cardiovascular disease, diabetes, hypercholesterolemia or obesity.

Description

technical field [0001] The invention provides the application of a class of resveratrol tetramer compounds in the preparation of medicines for the treatment or prevention of diseases or conditions related to liver X receptor (LXR) activity, including the prevention and treatment of neurodegenerative diseases, cardiovascular Disease, diabetes, high cholesterol, or obesity. Background technique [0002] Liver X receptor (LXR) is a transcription factor belonging to the nuclear receptor superfamily, and LXR receptor forms a heterodimer by connecting to the retinoid X receptor (RXR), and the heterodimer In a specific way, it binds to the DNA response element (LXRE) that causes the transcriptional activation of the target gene (Genes dev.1995; 9:1033-45). The LXR / RXR dimer can be activated using LXR and / or RXR ligands. At the same time, the transcriptional activation of target genes requires the addition of co-activators such as SRC-1 (Nature 1996, 383:728-31). [0003] This re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/343A61P25/28A61P9/00A61P3/10A61P3/04A61P3/06
Inventor 杜冠华李韶菁黄峰刘艾林蓝希林茂
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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