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Novel glucagon-like peptide-1(GLP-1) analogues and use thereof

A technology of glucagon and GLP-1, which is applied in the application field of new glucagon-like peptide-1 analogues, can solve problems such as peripheral edema, weight gain, hypoglycemia, etc., and achieve improved affinity, Prolong the action time and improve the effect of hypoglycemic activity

Active Publication Date: 2012-10-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the complexity of the etiology of diabetes, although the curative effect of these oral hypoglycemic drugs is definite, there are many deficiencies.
1. The pharmacological mechanism of sulfonylurea hypoglycemic drugs in the treatment of type 2 diabetes is non-glucose-dependent, which is likely to cause hypoglycemia; and because sulfonylurea drugs promote insulin secretion by blocking the potassium channel on the islet β-cells, This predisposes to further damage to islet β-cells
2. Thiazolidinediones may cause weight gain and peripheral edema and induce heart failure
3. Biguanide hypoglycemic agents such as metformin sometimes have dose-related gastrointestinal side effects, and patients with liver and kidney dysfunction are at risk of lactic acidosis
But the risk of hypoglycemia with insulin
Affected by factors such as dose size, injection site, injection route, individual differences, or not eating after injection, if insulin is used carelessly, severe hypoglycemia side effects will occur

Method used

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  • Novel glucagon-like peptide-1(GLP-1) analogues and use thereof
  • Novel glucagon-like peptide-1(GLP-1) analogues and use thereof
  • Novel glucagon-like peptide-1(GLP-1) analogues and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Gly 8 -GIu 22 -GLP-(7~36)-NH 2 (SEQ.ID NO: 2) microwave-facilitated solid-phase synthesis

[0031] (1) Swelling of the resin

[0032] Weigh 50mg of Fmoc-rink amide-MBHA Resin (substitution amount 0.4mmol / g), swell with 7mL DCM for 30min, filter to remove DCM, then swell with 10mL NMP for 30min, and finally rinse with NMP, DCM, and NMP 7mL respectively.

[0033] (2) Microwave promotes removal of Fmoc protecting group

[0034] Put the swollen resin into the reactor, add 7mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT, react in the microwave reactor for 1min, the microwave power is 15W, and the reaction temperature is controlled at 50°C Within the time period, use an air compressor to compress the air to cool, and filter the solution after the reaction; add 7 mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT and react in a microwave reactor for another 4 minutes, and the microwave power is 25W , the reaction temperature was controlle...

Embodiment 2～11

[0048] According to the method described in Example 1, the polypeptides of Examples 2-28 were synthesized according to the corresponding sequences, and their respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS).

Embodiment 2

[0050] His- Phe -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val -Lys-Gly-Arg-NH 2 (SEQ.ID NO: 3); The theoretical relative molecular mass is 3445.8. ESI-MS m / z: found[M+3H] 3+ 1149.4, [M+4H] 4+ 862.4, [M+4H+K] 5+ 697.6;calu[M+3H] 3+ 1149.6, [M+4H] 4+ 862.5, [M+4H+K] 5+ 697.8.

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Abstract

The invention relates to a novel GLP-1 analog and the application thereof. The GLP-1 analog with higher stability and higher hypoglycemic activity is obtained by reconstructing 8, 22 amino acid residue sites of natural GLP-1. The chemical synthesis is achieved at high efficiency and high speed by using microwave to promote solid phase synthesis, and the crude product is purified by a preparative grade HPLC and lyophilized to obtain the GLP-1 analog.

Description

technical field [0001] The present invention relates to a class of novel glucagon-like peptide-1 (GLP-1) analogues, a microwave-promoted solid-phase synthesis method thereof, and applications of the novel glucagon-like peptide-1 (GLP-1) analogues . Background technique [0002] Diabetes, especially type 2 diabetes, is the third chronic non-communicable disease that seriously threatens human health after tumors and cardiovascular diseases. Currently, there are about 200 million diabetics in the world, which is expected to increase to 300 million by 2025. In 2007, China had 40 million diabetic patients, second only to India with 40.9 million diabetic patients, ranking second in the world. It is estimated that by 2025, the number of diabetic patients in my country will exceed 60 million, of which type 2 diabetes accounts for about the total number of diabetic patients More than 90% of. [0003] Some existing oral hypoglycemic drugs are the main method for treating diabetes. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10
Inventor 黄文龙张惠斌迟玉石周金培周映红钱海倪帅键
Owner CHINA PHARM UNIV
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