Farnesoid X receptor agonist

A technology of agonists, drugs, applied in the field of medicine

Active Publication Date: 2018-12-18
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, among the adverse reactions of obeticholic acid, pruritus is the most common. In a clinical trial, 68% of patients in the oral 10mg treatment group and 56% of patients in the titrated 10mg treatment group experienced itching

Method used

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  • Farnesoid X receptor agonist
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The synthesis of embodiment 1 OBN-K

[0026]

[0027] 1. Synthesis of OBN

[0028] Add OBA (40g 0.095mol 1eq) into a 3L three-necked flask, then add acetone (400ml), stir and control the temperature between 0-10°C, add HOBT (21.9g 0.19mol 2.0eq), then add DCC (49g 0.24mol 2.5eq) and 4-dimethylaminopyridine (1.16g 0.95mmol 0.01eq), stirred for 0.5-2h, TLC, 115 disappeared, and an active ester was generated. Add taurine aqueous solution (24g 0.192mol 2eq) and triethylamine (20g 0.2mol 2eq) to the reaction solution, continue to stir the solution for 2-5h, add 6N HCl to adjust the pH of the reaction solution to be 1-2, and stir the reaction solution for 1 -2h, concentrate the solvent, filter the precipitate with suction, extract the filtrate with tetrahydrofuran, dry the organic phase with anhydrous sodium sulfate, and spin dry at 40°C to obtain the crude product of OBN (taurobeticholic acid), mix the crude product with silica gel, wash The deagent is dichloromethane:m...

Embodiment 2

[0031] Example 2 Determination of FXR agonistic activity

[0032] The FXR ligand-binding region (amino acids 105 to 472) was fused to COOH-terminal glutathione transferase (GST), and the fused GST-FXR protein was expressed in E. coli and purified by glutathione glass beads. For FRET testing, europium-labeled anti-GST [anti-GST—(Eu)] (Wallac, Gaithersburg, MD) labeled GST-FXR, steroid receptor coactivator-1 (SRC-1, amino acids 595 to 822) was treated with 6-polyhistidine tagged and expressed in Escherichia coli, purified by ion chromatography, biocylated and labeled with allophycocyanin fluorescent protein (APC) and conjugated with streptavidin. Fluorescence resonance energy occurs in solution when ligand-mediated FXR conformational changes in affinity for SRC-1 result in energy transfer from europium (excitation at 337nm and emission at 620nm) to APC (excitation at 620nm and emission at 665nm) Transferred, the results are expressed by the fluorescence ratio of APC to Europium...

Embodiment 3PB

[0037] Embodiment 3PBC model

[0038] Thirty-two SPF grade SD rats aged 6-8 weeks were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The experimental animals were kept in the SPF animal room. The animal room was well ventilated and equipped with air conditioning. The temperature was kept at 20-25°C, the humidity was kept at 40%-70%, the number of air changes was 10-15 times / h, and the light and dark lighting were 12 hours each. The experimental animals were free to eat and drink, and each rat was marked with an ear tag. The rats were randomly divided into two groups according to body weight: 24 rats in the bile duct ligation group and 8 rats in the sham operation group. After the rats in the bile duct ligation group were fasted overnight, the abdomen was shaved, and the animals were anesthetized with isoflurane inhalation. The abdomen was disinfected and incised along the abdominal midline to expose and free the common bile duct. Cut between t...

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Abstract

The present invention relates to a farnesoid X receptor agonist, and discloses a compound represented by the following formula represented in the specification. According to the present invention, thecompound OBN-K has agonistic effect on FXR, has the EC50 value comparable to the EC50 value of obeticholic acid, can significantly reduce the ALP level and the TBIL level in the serum of biliary cirrhosis rat models caused by bile duct ligation, can significantly improve the liver fibrosis score, has the PBC treatment effect comparable to the PBC treatment effect of obeticholic acid, can significantly decrease the ALT level and the AST level in the serum of MCD-induced NASH model rats and significantly improve the liver pathological NASH scores, has the NASH treatment effect comparable to theNASH treatment effect of obeticholic acid, and further has the significantly-reduced incidence of itching adverse reaction compared to obeticholic acid.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a farnesoid X receptor agonist, in particular to a small molecule farnesoid X receptor agonist, its preparation method and application. Background technique [0002] FXR (farnesoid X receptor) is a bile acid receptor expressed in tissues and organs such as the liver and intestine system, which can be activated by endogenous ligand bile acids, and plays an important role in bile acid metabolism and cholesterol metabolism, and can promote One of the most important pathways in the differentiation of fat cells in the body and the regulation of the function of fat cells in the body is the insulin pathway. The primary bile acid chenodeoxycholic acid is the most potent ligand for FXR, and the secondary bile acids lithocholic acid and deoxycholic acid can also activate FXR. Obeticholic acid is an FXR agonist and a bile acid regulator, which increases insulin secretion, improves insulin resistance, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00A61K31/575A61P9/12A61P1/12A61P1/16
CPCC07J41/0061
Inventor 袁建栋黄仰青隋巍峰
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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