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Polypeptide derivative combining DDP-4 inhibiting and GLP1R activating activities and preparation and application thereof

A compound, C1-C6 technology, applied in the field of medicine, can solve problems such as unfavorable drugs and complex structure, and achieve the effect of high inhibitory activity

Active Publication Date: 2019-04-12
LETO LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are some GLP1R agonists on the market, but their complex structure is not conducive to drug use. Therefore, it is necessary to use new mechanisms to develop new GLP1R agonists to improve efficacy, simplify structure and prolong half-life in vivo

Method used

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  • Polypeptide derivative combining DDP-4 inhibiting and GLP1R activating activities and preparation and application thereof
  • Polypeptide derivative combining DDP-4 inhibiting and GLP1R activating activities and preparation and application thereof
  • Polypeptide derivative combining DDP-4 inhibiting and GLP1R activating activities and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] 1 equivalent of N-tert-butoxycarbonyl (Boc) amino acid, 1 equivalent of the corresponding ethyl piperidine carboxylate, 1.2 equivalents of 2-(7-oxybenzotriazole)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (HATU) and 2 equivalents of triethylamine were dissolved in dichloromethane, stirred at room temperature for 8 hours, and the reaction was detected by thin layer chromatography (TLC). After the reaction was completed, dichloromethane and 1N hydrochloric acid aqueous solution were added, the organic phase was separated, washed three times with water, dried and concentrated, and the dichloromethane was evaporated in vacuo to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain ethyl N-Boc aminopiperidinecarboxylate amide. The intermediate was dissolved in dichloromethane, and trifluoroacetic acid was added to make trifluoroacetic acid:dichloromethane=1:10. The reaction was stirred at room temperature for 1 ho...

Embodiment 2

[0157] Example 2 Determination of Inhibitory Activity of Compounds on Human DPP-4 Enzyme in Vitro

[0158] Each compound was dissolved using DMSO (final concentration 50 ).

Embodiment 3

[0159] Example 3 Determination of Inhibitory Activity of Compounds on Human GLP1R Receptor in Vitro

[0160] Preparation of reagents:

[0161] Prepare Hanks equilibration buffer using raw materials and reagents listed in Table 3:

[0162] 1. Cremophor EL (3% PBS solution)

[0163] 2. Sulfinpyrazone (250mM DMSO solution)

[0164] 3. Fluo-4, AM (2mM DMSO solution)

[0165] 4. Serotonin (10mM DMSO solution)

[0166] HBSS calcium ion buffer: BSA 0.1%, sulfinpyrazone 250μM

[0167] Table 3. Materials and reagents required for GLP1R agonistic activity test

[0168]

[0169]

[0170] Experimental operation:

[0171] 1) Inoculate cells with high expression of GLP1R into 96 empty plates with black transparent bottom, and the cell density is about 30,000cells / 100μL / well. The 96-well plate was placed at 37°C and incubated overnight.

[0172] 2) Conduct the experiment the next day. The calcium ion buffer used for staining needs to be prepared immediately. The method is as...

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PUM

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Abstract

The present invention provides a novel bifunctional polypeptide-derived compound and a preparation and an application thereof. Specifically, the present invention discloses the whole new polypeptide-derived compound having a structure shown in a formula A, and a use thereof as a dipeptidyl peptidase-4 (DPP-4) inhibitor and a glucagon-like peptide 1 receptor (GLP1R) activator. The polypeptide exhibits good DPP-4 inhibiting activity and GLP1R activating activity, and has an application value for treating type 2 diabetes.

Description

technical field [0001] The present invention relates to the field of medicine, in particular, the present invention relates to a novel polypeptide derivative with both DPP-4 inhibitory and GLP1R activation activities and its preparation and application. Background technique [0002] Diabetes is a long-term chronic disease that affects the health of more than 300 million people worldwide. The World Health Organization (WHO) predicts that by 2030, diabetes will become the seventh leading cause of death in the world. [0003] There is a polypeptide in the human body that can regulate blood sugar, called glucagon-like peptide 1 (GLP-1), GLP-1 can stimulate the secretion of insulin, thereby playing a role in returning blood sugar levels to normal . 50%-70% of the glucose ingested orally by the human body is metabolized through the GLP-1 / insulin pathway. Therefore, GLP-1 is an important hypoglycemic polypeptide. However, the half-life of GLP-1 in the body is extremely short, o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07D401/12A61K31/4439A61K38/16A61P3/10
CPCA61P3/10C07D401/12C07K14/001A61K38/00
Inventor 李泉常晴冉运聪陶子夏黄飞
Owner LETO LAB CO LTD
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