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Long-acting glucagon-like peptide 1 (GLP-1) analogues and application thereof

A technology of glucagon and GLP-1, applied in the field of long-acting glucagon-like peptide-1 analogs, can solve the problems of loss of biological activity of GLP-1, loss of histidine residues, etc. The effect of hypoglycemic action time, biological half-life extension, and stability improvement

Inactive Publication Date: 2013-05-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The N-terminus of the GLP-1 molecule is the binding site with the GLP-1 receptor, and its histidine residue is lost, resulting in the complete loss of biological activity of GLP-1

Method used

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  • Long-acting glucagon-like peptide 1 (GLP-1) analogues and application thereof
  • Long-acting glucagon-like peptide 1 (GLP-1) analogues and application thereof
  • Long-acting glucagon-like peptide 1 (GLP-1) analogues and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069]

[0070] microwave-facilitated solid-phase synthesis

[0071] (1) Cysteine ​​synthesis with side chain modification

[0072] Weigh 0.21g of Fmoc-Cys-OH, dissolve it in DCM, add 0.37g of 3,3'-(4-(3-maleimidopropionamido)benzylidene)-di-4-hydroxy Coumarin, 5ul DIEA was used as a catalyst, and the reaction was stirred at room temperature for 5 hours. After the reaction was monitored by a thin-layer plate, the reaction liquid was concentrated under reduced pressure and separated by column chromatography to obtain 0.4 g of the product, with a yield of 83%.

[0073] MS (70eV) m / z: 944.3 ([M+Na] + ).

[0074] (2) Swelling of the resin

[0075] Weigh 50 mg of Fmoc-Rink amide-MBHA Resin (substitution amount 0.4 mmol / g), swell with 7 mL of DCM for 30 min, remove DCM by suction filtration, then swell with 10 mL of NMP for 30 min, and finally rinse with NMP, DCM, and 7 mL of NMP respectively.

[0076] (3) Microwave promotes removal of Fmoc protecting group

[0077] Put the ...

Embodiment 2～6

[0091] According to the method described in Example 1, the glucagon-like peptide-1 (GLP-1) analogues of Examples 2-6 were synthesized according to the corresponding sequence, and the respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS) .

Embodiment 2

[0093]

[0094] The theoretical relative molecular mass is 3836.7. ESI-MS m / z: found[M+4H] 4+ 960.2, [M+5H] 5+ 768.3;calu[M+4H] 4+ 959.6, [M+5H] 5+ 767.8

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Abstract

The invention relates to long-acting glucagon-like peptide 1 (GLP-1) analogues and a synthesis method thereof. GLP-1 analogues with longer pharmacological action time are obtained through replacing the 34th amino acid of natural GLP-1, the synthesis of target polypeptides is quickly realized through a microwave-promoted solid-phase synthesis method, and crude products are purified and freeze-dried to obtain the GLP-1 analogues.

Description

technical field [0001] The present invention relates to long-acting glucagon-like peptide-1 (GLP-1) analogs and applications thereof. Background technique [0002] Diabetes is the third chronic non-communicable disease that seriously threatens human health after tumors and cardiovascular diseases. Currently, there are about 300 million diabetics in the world, which is expected to increase to 500 million by 2025. In 2010, there were 92 million diabetics in China, and China has become the second largest country with diabetes after India, in which type 2 diabetes accounts for about 90% of the total number of diabetics. The most effective way to treat type 2 diabetes right now is insulin injections. Clinically, intensive insulin therapy is used to delay the progression of diabetes. Insulin therapy can reverse the damage of pancreatic β-cell function to a certain extent while lowering blood sugar. However, there is a risk of hypoglycemia with insulin. Affected by factors such...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61P3/10C07K1/06C07K1/04
Inventor 黄文龙钱海孙李丹韩京李政褚莹莹
Owner CHINA PHARM UNIV
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