Substituted benzamide liver X receptor (LXR) agonists and application

A technology of benzamide and agonist, applied in the pharmaceutical composition of the compound, the field of agonist of liver X receptor, can solve the problem that the mechanism has not yet been elucidated

Active Publication Date: 2014-11-19
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] In summary, at present, the importance of nuclear receptor LXRs signaling pathway has receive...

Method used

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  • Substituted benzamide liver X receptor (LXR) agonists and application
  • Substituted benzamide liver X receptor (LXR) agonists and application
  • Substituted benzamide liver X receptor (LXR) agonists and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1. N-methyl-N-(2-oxo-2-(2,3,4-trifluoroanilino)ethyl)-3,4-dihydrobenzo-1,5-diox Synthesis of Heterocyclic-7-Carboxamides

[0091]

[0092] Take 2,3,4-trifluorobenzamide (5.90g, 0.04mol) in a 100mL three-necked flask, add 40mL of tetrahydrofuran to dissolve it, and add 15mL of chloroacetyl chloride (4.52g, 0.04mol) dropwise at 0°C ) tetrahydrofuran solution, add 4.2mL (0.06mol) triethylamine after the dropwise addition, and stir at room temperature for 4h; 2 O (8.73g, 0.04mol) was stirred at room temperature for 12h. After evaporating the solvent, dissolve it with 40mL of dichloromethane, add 10mL of ammonia water, and react at reflux at 90°C for 12h. After the reaction is completed, evaporate to dryness and dissolve to obtain a yellow solid, dissolve it with 30ml of 5% hydrochloric acid at low temperature, wash the water phase with 20ml of ethyl acetate, then adjust the pH to 9 with saturated sodium carbonate in an ice bath, and precipitate a large amount o...

Embodiment 2

[0097] Example 2. Culture of cells

[0098] Both human liver cancer cells HepG2 and human colorectal adenocarcinoma cells Caco-2 are adherent cells. HepG2 was passaged every 48 hours, and Caco-2 was passaged every 96 hours. After the cells are full, discard the old medium, rinse the cells with PBS and discard, then add an appropriate amount of trypsin, digest HepG2 at room temperature for about 2 minutes, and digest Caco-2 at 37°C for 10 minutes, discard the digestion solution, and immediately Add complete MEM medium containing 10% FBS to inhibit the activity of trypsin, gently blow and tap the cells in the culture flask with an elbow pipette to completely detach the cells from the bottom of the bottle and disperse them into a single cell suspension by blowing and blowing. Then inoculate the cell suspension in a new cell flask at a ratio of 1:3, then add an appropriate amount of complete medium, and put it in an incubator to continue culturing. Culture conditions: 37°C, 5% CO...

Embodiment 3

[0101] Example 3. Determination of compound (I) agonistic activity on LXR

[0102] In this activity determination, the agonist screening model of LXR is used to measure the activity of the compound.

[0103] Measuring principle:

[0104] The principle of this assay is that, based on the two main domains in the LXR structure: Ligand Binding Domain (LBD) and DNA Binding Domain (DBD), and the fact that the transcription factor GAL4 in yeast has a similar structure to nuclear receptors, the application According to the principle of yeast two-hybrid, two plasmids are constructed respectively: pBIND-LXR plasmid contains the DBD part of the GAL4 gene and the LBD domain of LXR, which can change conformation when activated by ligand; the other plasmid is pGL4-GAL4, which contains the GAL4 gene Luciferase reporter gene Luc from the promoter region response element. We co-transfected the two plasmids into HepG2 cells to study the activation of LXR by the compounds. In this detection s...

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Abstract

The invention relates to a group of novel compounds serving as liver X receptor (LXR) agonists and a drug composition containing the compounds or medicinal salts thereof and also relates to methods for preparing the compounds and the composition. The invention discloses an application of the compounds as pharmacologically active substances, especially the important application to treatment of cardiovascular diseases such as atherosclerosis, hypertension, hyperlipidemia, hypercholesteremia and coronary heart diseases, metabolic syndromes such as obesity and diabetes mellitus, neurodegenerative diseases such as Alzheimer, immunity-related diseases and the like.

Description

technical field [0001] The invention relates to a group of substituted benzamide compounds and a preparation method, in particular to an agonist of the liver X receptor and its use. [0002] The invention also relates to pharmaceutical compositions of said compounds. Background technique [0003] Liver X receptors (LXRs) are ligand-activated transcription factors and belong to the nuclear receptor superfamily. LXRs were initially isolated from a human liver cDNA library by Willy in 1994 (P.J.Willy et al., LXR, a nuclear receptor that defines a distinct retinoid response pathway, Genes Dev9 (1995): 1033-1045.), which is related to retinoid Alcohol X receptor (Retinoid X receptor, RXR) forms a heterodimer, and when it binds to a ligand, it activates the expression of the target gene by binding to the regulatory region of the target gene. Since no natural ligands for LXRs were found at first, LXRs are also called "orphan receptors". The LXR subfamily includes two isoforms, L...

Claims

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Application Information

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IPC IPC(8): C07D321/10C07D471/04C07D215/48C07D237/32C07D295/155C07D317/68C07D239/90C07D495/04C07D209/12C07D405/12C07D319/18C07D211/58C07D401/12C07D401/06C07D209/48C07D403/06C07D487/04C07D405/06C07D417/06C07C237/42C07C231/12A61K31/357A61K31/4745A61K31/47A61K31/502A61K31/5375A61K31/5377A61K31/4365A61K31/4045A61K31/166A61K31/517A61K31/4468A61K31/5513A61K31/4709A61K31/36A61K31/4035A61K31/519A61K31/497A61K31/5415A61P9/10A61P9/12A61P3/06A61P9/00A61P3/04A61P3/10A61P3/00A61P25/28A61P37/02
CPCC07C231/12C07C237/42C07D209/12C07D209/48C07D211/58C07D215/48C07D237/32C07D239/90C07D295/155C07D317/68C07D319/18C07D321/10C07D401/06C07D401/12C07D403/06C07D405/06C07D405/12C07D417/06C07D471/04C07D487/04C07D495/04
Inventor 司书毅李霓李东升许艳妮李永臻刘畅冯婷婷姜威刘伟王智敏贺晓波巫晔翔王潇
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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