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Sodium ion taurocholic acid co-transporter peptide inhibitor

A technology of polypeptide inhibitors and ion cattle, applied in the field of sodium ion taurocholic acid co-transport polypeptide inhibitors

Inactive Publication Date: 2017-05-17
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The novel biotin-cholic acid / ursodeoxycholic acid compounds involved in the present invention have strong NTCP inhibitory activity, and as NTCP inhibitors, there have been no relevant reports at home and abroad so far

Method used

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  • Sodium ion taurocholic acid co-transporter peptide inhibitor
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  • Sodium ion taurocholic acid co-transporter peptide inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] "Example 1" Synthesis of N-Boc-N-methylethylenediamine-biotin (IV)

[0025] Biotin (II, 11.68g, 47.82mM), 1.5eq HOBt (9.69g), 2.0eq EDCI (18.34g) were added to 25mL of anhydrous dry DMF, and stirred for 2h. Then 2.0eq DIEA (15.78mL) and N-Boc-N-methylethylenediamine (III, 10.0g, 57.38mM) were added and stirred overnight. Add 500ml of water to quench. The reaction solution was extracted with DCM (3×150 mL), washed with 1N HCl (3×100 mL), 1N NaOH (3×100 mL) and saturated brine (2×100 mL). Anhydrous Mg for organic layer 2 SO 4 Dry, filter and spin dry to obtain white solid IV (14.52g), yield: 75.82%.

Embodiment 2

[0026] "Example 2" (V) synthesis of N-methylethylenediamine-biotin

[0027] Dissolve IV (10.01g, 25mM) in dichloromethane (60mL), pass dry hydrochloric acid gas at room temperature for 2.5h, and continue stirring for 1.5h. The reaction solution was spin-dried and vacuum-dried to obtain white solid V (8.34 g), yield: 99.1%.

Embodiment 3

[0028] "Example 3" Synthesis of CA-N-methylethylenediamine-biotin (I-1)

[0029] Add cholic acid (2.04g, 5mM), 1.5eq HOBt (1.08g), 2.0eq EDCI (1.98g) into 10mL of anhydrous dry DMF, and stir for 2h. Then 3.6eq DBU (2.79g) and V (1.52g, 4.51mM) were added and stirred overnight.

[0030] Add 500ml of water to quench. The reaction solution was extracted with DCM (3×30 mL), washed with 1N HCl (3×30 mL), 1N NaOH (3×30 mL), and saturated brine (2×40 mL), respectively. Anhydrous Mg for organic layer 2 SO 4 Dry, filter, and spin dry to obtain a yellow oily liquid, which is purified by a silica gel column to obtain I-1 as a white solid (1.76 g), yield: 51.2%.

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Abstract

The invention relates to synthesis of a novel sodium taurocholate cotransporting polypeptide (NTCP) inhibitor and inhibiting effects of the inhibitor on the NTCP. The experimental research indicates that the compound has high inhibition activity for NTCP and indicates directions for antivirus, anti-bile siltation and metabolic regulation effects of anti-bile acid transporting drugs. The compound or composition thereof is hopeful to be developed into a novel NTCP inhibitor with great potential.

Description

[0001] Technical field: [0002] The invention relates to the synthesis of biotin-cholic acid / ursodeoxycholic acid compound and its inhibitory effect on NTCP. [0003] Background technique: [0004] The sodium-taurocholate co-transporting polypeptide (NTCP) found on liver cells is a transporter encoded by the SLC10A1 gene and distributed on the basement membrane on the surface of liver cells. Important channel protein in circulation. Human NTCP protein contains 349 amino acids, molecular weight 56KDa, has 77% homology with rat NTCP protein, and contains 9 transmembrane regions. The vast majority of human NTCP protein is expressed in the liver, located in the basal side of hepatocytes. NTCP has a high transport affinity for conjugated cholate, and is the main channel protein for the liver to take up cholate from the blood, while maintaining a low level of cholate in the blood. [0005] Several studies have shown that the inhibition of NTCP can affect the enterohepatic circula...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00A61K31/58A61P31/20
CPCY02P20/55
Inventor 邵荣光蔡仕英王玉成王菊仙詹姆斯波义耳何红伟任金凤白晓光
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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