Long-acting exenatide derivative, salt thereof and preparation method and application
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A technology of exenatide and derivatives, applied in the field of exenatide derivatives, can solve problems such as prolonging the half-life of GLP-1, and achieve the effects of prolonging the biological half-life, prolonging the action time of hypoglycemic and weight loss, and being easy to purify
Active Publication Date: 2019-08-16
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD +1
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However, exenatide will still be rapidly filtered and eliminated in the kidney, and the deg
Method used
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Embodiment 1
[0049]
[0050] Synthesis
[0051] 1. Synthesis of peptide chains
[0052] 1.1 Resin swelling
[0053] Weigh 1g of 2-CTC Resin (degree of substitution 0.4mmol / g), swell with 10mL of DCM for 30min, filter to remove DCM, then swell with 10mL of NMP for 30min, rinse with NMP and 10mL of DCM respectively.
[0054] 1.2 Synthesis of Fmoc-Ser(tBu)-2-CTC Resin
[0055] Dissolve Fmoc-Ser(tBu)-OH (0.8mmol) and DIPEA (1.6mmol) in NMP10mL, then add this solution to the resin obtained in the previous step to react for 2 hours, filter the reaction solution after completion, and use DCM and NMP Wash the resin 3 times with 10 mL each.
[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, re...
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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Abstract
The invention relates to a long-acting exenatide derivative and belongs to the technical field of polypeptide compounds. The exenatide derivative long in pharmacologic action time is prepared by performing structural optimization on a exenatide sequence to allow the exenatide to have effects of lowering sugar and reducing weight, conjugating double-dose exenatide with single-dose fatty acid chain,and using the fatty acid chain to bring the serum albumin binding effect into play. The invention further discloses the preparation method of the exenatide derivative, the pharmaceutically acceptablesalt of the exenatide derivative, an exenatide derivative drug, a pharmaceutical composition and application of the exenatide derivative in the preparation of drugs for treating and/or preventing diabetes, obesity, hyperlipidemia and non-alcoholic fatty liver disease. The long-acting exenatide derivative can have a weight reducing effect on the basis that the sugar lowering activity of the exenatide derivative is kept, the biological half-life of the exenatide derivative is evidently prolonged as compared with the exenatide prototype, the biological half-life of part of the exenatide derivatives reaches more than 36 hours, and the sugar-lowering and weight-reducing action time is prolonged greatly.
Description
technical field [0001] The present invention relates to the technical field of polypeptide compounds, in particular to an exenatide derivative, a preparation method thereof, a drug administration compound and its use as a 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 p...
Claims
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