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Novel LXR agonist as well as preparation method and application thereof

A technology for uses and medicinal salts, applied in the field of new compounds, which can solve problems such as the inability to regulate the expression of human CYP7A1 gene

Inactive Publication Date: 2012-04-25
NCPC NEW DRUG RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the human CYP7A1 gene does not contain LXRE, so LXR cannot regulate the expression of the human CYP7A1 gene

Method used

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  • Novel LXR agonist as well as preparation method and application thereof
  • Novel LXR agonist as well as preparation method and application thereof
  • Novel LXR agonist as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The cultivation of embodiment 1 bacterial classification

[0064] Slant medium: PDA medium.

[0065] Seed medium: 2% starch, 1% glucose, 0.2% hot-pressed soybean meal powder, 0.6% malt powder, 0.3% yeast powder, 0.2% NaCl, MgSO 4 .7H 2 O 0.1%, CaCO 3 0.2% pH 7.0.

[0066] Fermentation medium: The rice medium is 2.5g of soybean flour per 100g of rice.

[0067] The slant of the fungus CGMCC No.2037 was inoculated in the seed medium, and after 72hr cultivation at 27°C, it was inserted into a 750ml Erlenmeyer flask with a content of 100g of rice medium, and cultivated in a solid medium for 14 days.

Embodiment 2

[0068] Example 2 The separation and structure of compounds (I), (II) and (III)

[0069] CGMCC No.2037 solid culture 4kg, soaked in 4000ml ethyl acetate for 2 hours, the ethyl acetate layer was washed with anhydrous Na 2 SO 4 After dehydration, concentration and drying, 23.0 g of brown substance was obtained.

[0070] Take 22.0g sample, dissolve and mix the sample, carry out silica gel medium pressure column (φ3.5×50cm) chromatographic separation, the elution condition is 100% petroleum ether to 100% acetone (different ratio) stage elution, collect and combine activity Components were concentrated and dried to obtain a brown solid.

[0071] Take the above active substance, use ODS reversed-phase column (PHENOMENEX ODSφ21.2×250mm) to carry out single-component preparation on preparative HPLC [mobile phase is CH 3 CN-(1‰H 3 PO 4 )H 2 O (80:40), flow velocity is 16ml / min, detection wavelength is 254nm], obtains compound (I) 256.2mg, compound (II) 30.0mg and compound (III) 25...

Embodiment 3

[0092] Example 3 Agonistic activity on LXR

[0093] This activity assay is an assay for the transcriptional activation of GAL4-LXR:

[0094] Assay principle: This mechanism utilizes the two main structural domains shared in the structure of LXR: the independence of the ligand-binding domain (LBD) and the DNA-binding domain (DBD) function, and the yeast cell transcription factor GAL4 has a nuclear receptor The ligand-binding domain (LBD) of LXR was fused with the DNA-binding domain (DBD) of yeast cell transcription factor GAL4 to express a chimeric protein, which was co-transfected with a reporter plasmid containing a GAL4-specific response element , to evaluate the activity of LXR ligands by measuring the expression of the reporter gene. According to this principle, the expression plasmid and reporter plasmid were constructed: the LXR-LBD fragment amplified by PCR from liver tissue was connected to the expression vector pBIND by double enzyme digestion to construct the pBIND-...

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Abstract

The invention relates to novel compounds as LXR receptor stimulating agents and a medicament composition containing the compounds or pharmaceutically acceptable salt thereof and also relates to a method for preparing the compounds and the medicament composition thereof. The invention discloses application of the compounds as pharmacological active substances, in particular application in treatingcardiovascular diseases such as hypertension, hyperlipemia, hypercholesterolemia, atherosclerosis and coronary heart disease, as well as inflammation, adiposis, diabetes, metabolic syndrome and the like.

Description

technical field [0001] The present invention relates to a new class of compounds, in particular to agonists of the liver X receptor. Background technique [0002] Liver X-activated receptors (LXRs) were initially reported by Willy in 1995 as a regulator of cholesterol metabolism, and were named because they are most abundantly expressed in the liver [Genes Dev.1995May 1; 9(9): 1033-45] . LXRs are members of the nuclear receptor superfamily, including LXRα (NR1H3) and LXRβ (NR1H2), with 77% homology and the same endogenous ligands. LXRβ is widely expressed, while LXRα is mainly distributed in the liver, adipose tissue, small intestine and macrophages. After LXRs are activated by ligands, they first form LXR / RXR heterodimers with retinoid X re-ceptorα, and then bind to the specific LXR response element (LXRE) on the target gene. Regulate the expression of this gene. LXRE is a repeating sequence composed of AGGTCA, with 4 bases in between [J BiolChem, 1997, 272, 3137~3140] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/14C07D487/14A61K31/519A61P9/00A61P29/00A61P3/06A61P3/04A61P3/10C12P15/00C12R1/66
Inventor 路新华郑智慧李业英可爱兵马瑛崔晓兰石英朱京童任晓林洁丁彦博穆栋徐岩曹林张雪莲单越琦蔡超静范玉玲张华贺建功
Owner NCPC NEW DRUG RES & DEV