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A class of long-acting hypoglycemic and weight-reducing peptides, its preparation method and its use as medicine

A drug and pharmacy technology, applied in chemical instruments and methods, drug combinations, medical preparations containing active ingredients, etc., can solve problems such as weak hypoglycemic activity and short half-life

Active Publication Date: 2021-08-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with pure GLP-1R agonists, OXM has a better effect in intervening body weight, regulating lipid metabolism, and improving glucose tolerance, but its hypoglycemic activity is relatively weak and its half-life is short

Method used

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  • A class of long-acting hypoglycemic and weight-reducing peptides, its preparation method and its use as medicine
  • A class of long-acting hypoglycemic and weight-reducing peptides, its preparation method and its use as medicine
  • A class of long-acting hypoglycemic and weight-reducing peptides, its preparation method and its use as medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060]

[0061] solid phase synthesis

[0062] 1. Synthesis of peptide chains

[0063] 1.1 Resin swelling

[0064] Weigh 50mg of Fmoc-Rink amide-MBHA Resin (degree of substitution: 0.4mmol / g), swell with 7mL of DCM for 30min, filter to remove DCM, then swell with 10mL of NMP for 30min, rinse with NMP and 7mL of DCM respectively.

[0065] 1.2 Removal of Fmoc protecting group

[0066] Put the swollen resin into the reactor, add 25% piperidine / NMP (V / V) solution containing 0.1M HOBt to the resin to remove Fmoc, and wash it with NMP after the reaction. 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 (15.4 mg, 0.04 mmol), HBTU (15.1 mg, 0.04 mmol), HOBt (5.4 mg, 0.04 mmol) and DIPEA (13.9 μL, 0.08 mmol) were dissolved in NMP 10 mL, and then This solution was added to the resin obtained in the previous step, and reacted for 2 hours. After completion, the reaction...

Embodiment 2

[0079]

[0080] 1. Synthesis of 16-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)hexadecanoic acid

[0081] 16-Aminohexadecanic acid (1.09g, 4mmol) and maleic anhydride (0.47g, 4.8mmol) were dissolved in glacial acetic acid, and after ultrasonic dissolution, they were refluxed at 120°C for 6h. After the reaction was completed by TLC, the reaction The liquid was cooled to room temperature, extracted three times with ethyl acetate (3×20mL), the upper layer extracts were combined, and the extracts were washed three times with saturated brine, anhydrous Na 2 SO 4 Let dry overnight. The extract was spin-dried in vacuo to obtain a crude product, which was separated by column chromatography (ethyl acetate / petroleum ether) to obtain 1.02 g of a light yellow pure product with a yield of 72%.

[0082] 1 H-NMR (DMSO-d 6 , 300MHz): δppm: 12.45(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...

Embodiment 3

[0086]

[0087] 1. Synthesis of chemical modification groups

[0088] Synthesis of 3,3'-(4-carboxybenzylidene)-di-4-hydroxycoumarin

[0089] p-Carboxybenzaldehyde (0.45g, 3mmol) was dissolved in 20ml of absolute ethanol, and then 4-hydroxycoumarin (0.98g, 6mmol) was added. After heating to reflux for 12 hours, the reaction solution was cooled to room temperature and then filtered, and the filter cake was washed 3 times with 10ml of ethanol to obtain 1.12g of the product, with a yield of 82.1%, ESI-MS m / z: 456.4[M+H] + .

[0090] Synthesis of tert-butyl (12-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)dodecyl)carbamate

[0091] Dissolve N-Boc-dodecyldiamine (1.2g, 4mmol) and maleic anhydride (0.49g, 4.8mmol) in glacial acetic acid, heat the reaction at 120°C for 6h, after the TLC detection reaction is complete, the reaction The liquid was cooled to room temperature, extracted with ethyl acetate (3×20mL), the upper layer extracts were combined, and the extracts were washed 3 time...

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Abstract

The invention relates to a long-acting hypoglycemic and weight-reducing gastric oxyntomodulin (OXM) hybrid peptide and its application and synthesis method. By changing the peptide sequence of OXM and hybridizing with the peptide sequence of Exenatide, the OXM hybrid peptide with longer pharmacological action time and better weight loss effect is obtained. The synthesis of the target polypeptide is quickly realized through the solid-phase synthesis method of the orthogonal protection strategy, and the crude product is purified and freeze-dried to obtain the target compound.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of long-acting hypoglycemic and weight-reducing peptides, its preparation method 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] Oxyntomodulin (OXM) is a polypeptide composed of 37 amino acids secreted by small intestinal L cells, including the entire 29 amino acid sequence of glucagon and the 8 amino acid part of the C-terminal extension, which is similar to glucagon Peptide-1 (GLP-1) has 50% homology, and the peptide sequence is: HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA. OXM can simultaneously activate glucagon-like peptide-1 recep...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K38/22A61K38/26A61P3/10A61P3/04A61P3/06A61P1/16
CPCA61P1/16A61P3/04A61P3/06A61P3/10C07K14/57563C07K14/605A61K38/00C07K2319/00
Inventor 钱海黄文龙李承业蔡星光戴雨轩孙李丹刘春霞
Owner CHINA PHARM UNIV
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