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Hypoglycemic peptide and application thereof

A hypoglycemic and m-aa3 technology, applied in the field of medical biochemistry, can solve problems such as unstable effects

Active Publication Date: 2019-04-30
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its effect is unstable, and there are certain limitations in its use.

Method used

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  • Hypoglycemic peptide and application thereof
  • Hypoglycemic peptide and application thereof
  • Hypoglycemic peptide and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Example 1: Synthesis of 2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl substituted carboalkanoic acids,

[0090] Method 1.1: Synthesis of 12-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)dodecanoic acid

[0091] Weigh 12-aminododecanoic acid (2151.9 mg) and dissolve it in a three-neck flask with acetic acid, weigh maleic anhydride (980.6 mg) and dissolve it with acetic acid, and slowly add it dropwise to the above solution using a constant pressure dropping funnel , heated to reflux at 120° C. for 6 h, distilled off the solvent under reduced pressure, and purified by basic alumina column chromatography (gradient elution of ethyl acetate / petroleum ether) to obtain a white powdery solid with a yield of 81.9%.

[0092] 1 H-NMR (DMSO-d 6 ,300MHz):δppm:12.42(s,1H,-COO H ),7.50(s,2H,-COC H =C H CO-),3.88(t,2H,J=7.0Hz,-NC H 2 -),2.68(t,J=7.3Hz,2H,-C H 2 COOH),2.00-1.96(m,4H,-NCH 2 C H 2 (CH 2 ) 7 C H 2 ),1.73(s,14H,-NCH 2 CH 2 (C H 2 ) 7 CH 2 ).MS(ESI,m / z):294.1[M-H] - , m...

Embodiment 2

[0097] Embodiment 2: the preparation method of compound X

[0098] The reaction scheme is as follows:

[0099]

[0100] Method 2.1: Synthesis of 12-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)dodecanoyl)-L-glutamic acid

[0101] a) Swelling of 2-CTC resin

[0102]Weigh 2-CTC resin (363.6mg, degree of substitution 0.55mmol / g) into a polypeptide reaction tube, swell with dichloromethane for 30min, wash the resin 3-5 times with dichloromethane, filter and dry for later use.

[0103] b) Synthesis of X-1

[0104] Dissolve Fmoc-Glu(otBu)-OH (255.3mg) and DIPEA (1.6mmol, 264μL) in about 7mL of dichloromethane, pour the solution into the above resin, react at room temperature, bubble nitrogen for 4h, methanol / DIPEA= 9:1 ​​Head sealing for 30 minutes.

[0105] c) Synthesis of X-2

[0106] Wash the above resin three times with DMF and dichloromethane respectively, add about 10 mL of deprotection agent to the reactor, react at room temperature, bubble nitrogen for 30 min, and filter to...

Embodiment 3

[0129] Example 3 Polypeptide Chain Synthesis

[0130] 3.1

[0131] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Cys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Tyr-Ile-Gln-Trp- Leu-Lys-Glu-Gly-Gly-Pro-Ser-Ser-Gly-Arg-Pro-Pro-Pro-Ser-NH 2

[0132] a) Resin swelling

[0133] Weigh Fmoc-Rink amide-MBHA resin (18.2g, degree of substitution 0.55mmol / g) and place it in a polypeptide reaction tube. After swelling with dichloromethane for 30min, wash it three times with methanol and dichloromethane respectively, and store it for later use.

[0134] b) Removal of 9-hut methoxycarbonyl (Fmoc)

[0135] Preparation of deprotecting agent: Weigh HOBt (6.75g), dissolve it in 400mL of DMF, add 100mL of piperidine, and mix well. Deprotection was performed in two steps. For the first time, add about 50mL of deprotection agent and bubble nitrogen to make the resin fully contact with the deprotection agent. After 30 minutes of deprotection, filter out the deprotection agent, add about 50mL of new de...

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Abstract

The invention relates to a hypoglycemic peptide and an application thereof. A long-acting derivative is obtained by structural modification of insulin. The invention also discloses a novel compound used for modification and a preparation method thereof, and the hypoglycemic peptide of the invention is synthesized by solid phase synthesis by an orthogonal protection strategy, the synthesis method is simple, and the synthesis speed is fast. Moreover, the hypoglycemic peptide has the significant hypoglycemic effect and a long acting time.

Description

technical field [0001] The invention relates to the field of medical biochemistry, in particular to the design and application of a novel long-acting hypoglycemic peptide in the field of diabetes treatment. 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 also affected by factors such as dose, injection site, and injection route, and there are large individual differences. If insulin is slightly inadvertent, 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 hypoglyc...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07D207/452A61K38/22A61P3/10
CPCA61K38/00A61P3/10C07D207/452C07K14/575
Inventor 钱海徐丹黄文龙蔡星光李承业
Owner CHINA PHARM UNIV
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