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A class of exenatide (exendin-4) analogs with ether linkages and their applications

A technology of exenatide and analogs, which is applied to a class of exendin-4 analogs with ether bonds and their application fields, can solve the problems of prolonging the half-life of GLP-1 and the like, and increase the water solubility. Sex, avoid local itching, improve the effect of receptor agonist activity

Active Publication Date: 2021-01-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since GLP-1 is rapidly filtered and eliminated by the kidneys, resistance to degradation by DPP-IV enzymes can only prolong the half-life of GLP-1 to a certain extent

Method used

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  • A class of exenatide (exendin-4) analogs with ether linkages and their applications
  • A class of exenatide (exendin-4) analogs with ether linkages and their applications
  • A class of exenatide (exendin-4) analogs with ether linkages and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060]

[0061] solid-phase synthesis.

[0062] 1. Synthesis of cysteine-modified polypeptide chain

[0063] 1.1. Resin swelling

[0064] Weigh 50 mg of Fmoc-Rink amide-MBHA Resin (degree of substitution 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.

[0065] 1.2. Removal of Fmoc protecting group

[0066] Put the swollen resin into the reactor, add 7 mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBt, react for 1 min, and filter off the solution after completion; then add 25% piperidine containing 0.1M HOBt Pyridine / NMP (V / V) solution 7mL, reacted for 4min, filtered off the solution after completion, washed with NMP. A resin free of the initially attached Fmoc protecting group is obtained.

[0067] 1.3. Synthesis of Fmoc-Ser(tBu)-Rink amide-MBHA Resin

[0068] Fmoc-Ser(tBu)-OH (15.3 mg, 0.04 mmol), HBTU (15.1 mg, 0.04 mmol), HOBt (5.4 mg, 0.04 mmo...

Embodiment 2

[0091]

[0092] The synthesis method is the same as in Example 1, and the theoretical relative molecular mass is 5028.2. ESI-MS m / z: Calcd.[M+3H] 3+ 1677.1, [M+4H] 4+ 1258.1; Found[M+3H] 3+ 1677.4, [M+4H] 4+ 1258.2.

Embodiment 3

[0094]

[0095] The synthesis method is the same as in Example 1, and the theoretical relative molecular mass is 5015.1. ESI-MS m / z: Calcd.[M+3H] 3+ 1672.7, [M+4H] 4+ 1254.8; Found[M+3H] 3+ 1672.5, [M+4H] 4+ 1254.8.

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PUM

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Abstract

The present invention relates to a class of exendin-4 analogs with ether bonds and a synthesis method thereof. Exendin-4 analogs with longer pharmacological action time are obtained by transforming Exendin-4. The synthesis of the target polypeptide is achieved by solid-phase synthesis with an orthogonal protection strategy. The crude product is purified and freeze-dried to obtain Exendin-4 analogs. thing.

Description

technical field [0001] The invention relates to a class of exenatide (Exendin-4) analogs with ether bonds in the field of diabetes treatment 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. Clinically, intensive insulin therapy is used to delay the progression of diabetes, but insulin injections have the risk of hypoglycemia. The therapeutic effect is affected by factors such as dose, injection site, and injection route, and there are large individual differences. If insulin is used carelessly, severe hypoglycemic side effects will occur. [0003] Glucagon-like peptide-1 (GLP-1) is a glucose-dependent incretin hormone. GLP-1 stimulates insulin secretion without hypoglycemia. This glucose-dependent insulin-stimulating p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575A61K38/22A61P3/10
CPCA61K38/00C07K14/57563
Inventor 黄文龙钱海孙李丹蔡星光韩京毕昕洲刘春霞戴雨轩
Owner CHINA PHARM UNIV
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