Long-acting Exenatide Derivatives and Salts, Preparation Methods and Applications

A technology of exenatide and its derivatives, which is applied in the field of exenatide derivatives, can solve the problems of prolonging the half-life of GLP-1, achieve the goal of reducing blood sugar and slowing down, low production cost, and prolonging the time of hypoglycemic and weight loss. Effect

Active Publication Date: 2021-07-23
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, exenatide will still be rapidly filtered and eliminated in the kidney, and the degradation of anti-DPP-IV enzymes can only prolong the half-life of GLP-1 to a certain extent

Method used

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  • Long-acting Exenatide Derivatives and Salts, Preparation Methods and Applications
  • Long-acting Exenatide Derivatives and Salts, Preparation Methods and Applications
  • Long-acting Exenatide Derivatives and Salts, Preparation Methods and Applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050] Synthesis

[0051] 1. Synthesis of Peptide Chains

[0052] 1.1 Resin swelling

[0053] Weigh 1 g of 2-CTC Resin (degree of substitution 0.4 mmol / g), swell with 10 mL of DCM for 30 min, filter to remove DCM, then swell with 10 mL of NMP for 30 min, rinse with NMP and 10 mL of DCM respectively.

[0054] 1.2 Synthesis of Fmoc-Ser(tBu)-2-CTC Resin

[0055] Dissolve Fmoc-Ser(tBu)-OH (0.8 mmol) and DIPEA (1.6 mmol) in 10 mL of NMP, and then add this solution to the resin obtained in the previous step to react for 2 hours. and NMP 10 mL each to wash the resin 3 times.

[0056] 1.3 Removal of Fmoc protecting group

[0057] 25% piperidine / NMP (V / V) solution containing 0.1 M HOBt was added to the washed resin to remove Fmoc. After the reaction, the resin was washed 3 times with 10 mL each of DCM and NMP.

[0058] 1.4 Peptide chain extension

[0059] According to the sequence of the exenatide derivative peptide chain, repeat the above deprotection and coupling st...

Embodiment 2

[0067]

[0068] The synthesis method was the same as in Example 1, and the collected solution was lyophilized to obtain 24.9 mg of the pure product. The theoretical relative molecular mass is 8654.6. ESI-MS m / z: Calcd. [M+5H] 5+ 1731.9, [M+6H] 6+ 1443.4; Found [M+5H] 5+ 1732.1,[M+6H] 6+ 1443.7.

Embodiment 3

[0070]

[0071] The synthesis method was the same as in Example 1, and the collected solution was lyophilized to obtain 26.5 mg of the pure product. The theoretical relative molecular mass is 8738.8. ESI-MS m / z: Calcd. [M+5H] 5+ 1748.8, [M+6H] 6+ 1457.5; Found [M+5H] 5+ 1748.9,[M+6H] 6+ 1458.0.

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PUM

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Abstract

The invention is a long-acting exenatide derivative, which belongs to the technical field of polypeptide compounds. The exenatide derivative is structurally optimized for the exenatide sequence, so that it has hypoglycemic and weight-reducing effects at the same time, and double the amount of exenatide is conjugated with a single amount of fatty acid chains. The fatty acid chain plays a binding role with serum albumin to obtain exenatide derivatives with longer pharmacological action time. The invention also discloses a preparation method of exenatide derivatives, a pharmaceutically acceptable salt of exenatide derivatives, a pharmaceutical composition of exenatide derivatives, a pharmaceutical composition and a use thereof. Application of the derivative in the preparation of medicines for treating and / or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver. The long-acting exenatide derivatives can reduce the weight on the basis of retaining the hypoglycemic activity, and the biological half-life is significantly longer than that of the exenatide prototype, and some of them have reached more than 36 hours, which greatly prolongs the hypoglycemic effect. Time of bariatric action.

Description

technical field [0001] The present invention relates to the technical field of polypeptide compounds, in particular to an exenatide derivative, its preparation method, pharmaceutical composition and its use as medicine. Background technique [0002] The cause of metabolic syndrome is abnormal metabolism of various substances such as protein, fat and carbohydrates. Overnutrition and reduced physical activity can lead to obesity and obesity-related diseases such as diabetes. In recent years, the incidence of type 2 diabetes and dyslipidemia has been increasing day by day. [0003] Glucagon-like peptide-1 (GLP-1) is a glucose-dependent incretin hormone. It can stimulate the GLP-1 receptor and play a hypoglycemic effect. The most notable function is to promote the regeneration and repair of β-cells, increase the number of β-cells in the pancreas, and at the same time avoid the risk of hypoglycemia that often occurs in diabetes treatment. It has broad application prospects in ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K1/06C07K1/04C07K1/107A61K38/22A61P3/04A61P3/10A61P3/06A61P1/16
CPCA61K38/00A61P1/16A61P3/04A61P3/06A61P3/10C07K14/57563
Inventor 谷海涛赵呈青王蔡典姜建军
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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