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

A glucagon and GLP-1 technology, applied in the field of novel long-acting glucagon-like peptide-1 analogs, can solve the problems of loss of biological activity of GLP-1, loss of histidine residues, etc. Significant effect, hypoglycemic effect, effect of long plasma half-life

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102]

[0103] microwave-facilitated solid-phase synthesis

[0104] (1) Small molecule modified cysteine ​​synthesis

[0105] Weigh 0.21g of Fmoc-Cys-OH, dissolve it in DCM, add 0.18g 7-(6-maleimidopropionyl)-7-hydroxycoumarin, 8ul DIEA as a catalyst, and stir at room temperature After reacting for 4 hours, after the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain 0.33 g of the product, with a yield of 83%.

[0106] MS (70eV) m / z: 720.5 ([M+Na] + ).

[0107] (2) Swelling of the resin

[0108] 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 to remove DCM, then swell with 10 mL of NMP for 30 min, and finally rinse with NMP, DCM, and 7 mL of NMP respectively.

[0109] (3) Microwave promotes removal of Fmoc protecting group

[0110] Put the swollen resin into the reactor, add 7mL of 25% piperidine / NM...

Embodiment 2～16

[0124] According to the general method described in Example 1, the glucagon-like peptide-1 (GLP-1) analogs of Examples 2 to 16 were synthesized according to the corresponding sequences, and the respective analogues were confirmed by electrospray mass spectrometry (ESI-MS). molecular weight.

Embodiment 2

[0126]

[0127] The theoretical relative molecular mass is 3668.8. ESI-MS m / z: found[M+4H] 4+ 918.2, [M+5H] 5+ 734.7;calu[M+4H] 4+ 917.9, [M+5H] 5+ 734.3

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Abstract

The invention relates to novel 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 / modifying 17th, 26th, 34th and 37th amino acids 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 the GLP-1 analogues.

Description

technical field [0001] The present invention relates to novel 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 factor...

Claims

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Application Information

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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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