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

[0065]

[0066] Microwave-Promoted Solid-Phase Synthesis

[0067] (1) Cysteine ​​synthesis by side chain modification

[0068] Weigh 0.21g of Fmoc-Cys-OH, dissolve it in DCM, add 0.29g of 3,3'-(4-(6-maleimidopropionamido)benzylidene)-di-4-hydroxyl Beansine, 4ul DIEA was used as a catalyst, and the reaction was stirred at room temperature for 4 hours. After the completion of the TLC monitoring reaction, the reaction solution was concentrated under reduced pressure, and the product was separated by column chromatography to obtain 0.4 g of the product with a yield of 74%.

[0069] MS(70eV)m / z: 986.5([M+Na] + ).

[0070] (2) Swelling of resin

[0071] Weigh 50 mg of Fmoc-Rink amide-MBHA Resin (substitution amount 0.4 mmol / g), swell with 7 mL of DCM for 30 min, filter off DCM with suction, swell with 10 mL of NMP for 30 min, and rinse with 7 mL of NMP, DCM and NMP respectively.

[0072] (3) Microwave promotes the removal of Fmoc protecting group

[0073] Put the swollen res...

Embodiment 2～4

[0087] According to the method described in Example 1, the glucagon-like peptide-1 (GLP-1) analogs of Examples 2 to 4 were synthesized according to the corresponding sequences, and the respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS). .

Embodiment 2

[0089]

[0090] The theoretical relative molecular mass is 4007.9. ESI-MS m / z: found[M+4H] 4+ 1002.9, [M+5H] 5+ 802.6; calu[M+4H] 4+ 1002.4, [M+5H] 5+ 802.2

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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 adding a modified 37th amino acid to 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 a long-acting glucagon-like peptide-1 (GLP-1) analog and its application. Background technique [0002] Diabetes is the third most serious chronic non-communicable disease that threatens human health after cancer and cardiovascular disease. Currently, there are approximately 300 million people with diabetes worldwide, which is expected to increase to 500 million by 2025. In 2010, there were 92 million diabetic patients in China, and China has become the second largest country with diabetes after India, among which type 2 diabetes accounts for about 90% of the total number of diabetic patients. The most effective treatment for type 2 diabetes right now is insulin injections. Intensive insulin therapy is used clinically to delay the progression of diabetes. Insulin therapy can reverse the damage of islet β-cell function to a certain extent while reducing blood sugar. But with insulin there is a risk of hypoglycemia. A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10
Inventor 黄文龙钱海韩京孙李丹李政褚莹莹
Owner CHINA PHARM UNIV
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