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Glucagon-like peptide-1 (GLP-1) analogs, and preparation method and application thereof

A technology for glucagon and analogues, which is applied in the field of application of glucagon-like peptide-1 analogues and their dimers, medicines, and can solve problems such as medication compliance that needs to be improved to achieve improved clinical application Compliance, avoiding safety risks, overcoming short half-life effects

Active Publication Date: 2017-10-10
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although liraglutide greatly prolongs the half-life of GLP-1 in vivo, it still needs to be injected once a day, and the medication compliance still needs to be improved

Method used

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  • Glucagon-like peptide-1 (GLP-1) analogs, and preparation method and application thereof
  • Glucagon-like peptide-1 (GLP-1) analogs, and preparation method and application thereof
  • Glucagon-like peptide-1 (GLP-1) analogs, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Preparation of GLP-1 Analog Monomers and Dimers

[0054] A. Preparation of GLP-1 analogue monomer:

[0055] 1) synthesis: adopt Fmoc method, carry out synthesis method step by step according to the following steps:

[0056] a) Fmoc-Arg-resin is obtained by coupling an amino resin solid-phase support and Fmoc-protected arginine in the presence of an activator system;

[0057] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain N-terminal Fmoc-protected and side chain-protected peptide-resin conjugates; amino acids with side chains are protected as follows: tryptophan with tert-butoxy Carbonyl (Boc), glutamic acid tert-butyl (OtBu), lysine tert-butoxycarbonyl (Boc), glutamine trityl (Trt), tyrosine tert-butyl (tBu ), trityl (Trt) or tert-butyl (tBu) for serine, oxygen-tert-butyl (OtBu) for aspartic acid, tert-butyl (tBu) for threonine, trityl for histidine group (Trt) or tert-butoxycar...

Embodiment 2

[0069] Example 2 Preparation of GLP-1 analogue dimer with N-terminal acylation

[0070] 1) According to the monomer synthesis method in Example 1, a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection was synthesized;

[0071] 2) Remove the N-terminal Fmoc protecting group by conventional methods, suspend the resin-peptide conjugate in an appropriate amount of pyridine, add acetic anhydride or trifluoroacetic anhydride in an appropriate molar ratio, mix well, and place it to obtain the N-terminal histidine acyl Peptide-resin conjugates;

[0072] 3) Cleavage according to the method in Example 1 to obtain the crude peptide, purify, and lyophilize to obtain the monomeric target peptide;

[0073] 4) Prepare the dimer according to the method of Example 1.

[0074] The GLP-1 analog dimer formed by the following sequence monomers was prepared according to the above method:

[0075] GLP-1 analog dimer 3-3 formed by SEQ ID NO 3 and SEQ ID NO 3,

[00...

Embodiment 3

[0082] Example 3 Preparation of GLP-1 Analog Monomers and Dimers

[0083] A. Preparation of GLP-1 analogue monomer:

[0084] 1) synthesis: adopt Fmoc method, carry out synthesis method step by step according to the following steps:

[0085] a) In the presence of an activator system, Fmoc-Gly-resin is obtained by coupling an amino resin solid-phase support and Fmoc-protected glycine;

[0086] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain N-terminal Fmoc-protected and side chain-protected peptide-resin conjugates; amino acids with side chains are protected as follows: tryptophan with tert-butoxy Carbonyl (Boc), glutamic acid tert-butyl (OtBu), lysine tert-butoxycarbonyl (Boc), glutamine trityl (Trt), tyrosine tert-butyl (tBu ), trityl (Trt) or tert-butyl (tBu) for serine, oxygen-tert-butyl (OtBu) for aspartic acid, tert-butyl (tBu) for threonine, trityl for histidine group (Trt) or tert-butoxycar...

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Abstract

The invention provides glucagon-like peptide-1 (GLP-1) analog monomer peptides. The monomer peptides have the general formula 1: Z1HAX1GTFTSDVSSYLE X2QAAKEFICWLVKGRX3, wherein Z1 is hydrogen, acetyl or trifluoroacetyl; X1 is Met, Leu, Pro, Phe or Tyr; and X2 is Gly, Glu or Aib (2-aminoisobutyric acid). The invention also provides a dimer formed by the monomer peptides, a preparation method of the dimer, and application of the dimer in preparing drugs. The dimer of the GLP-1 analog monomers provided by the invention has the obvious effect of lowering the blood sugar, and the in vivo half life can reach 12-72 hours or above, thereby solving the problem of short half life in the natural GLP-1, and greatly enhancing the clinical application compliance.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a long-acting glucagon-like peptide-1 (GLP-1) analogue and a dimer thereof. The present invention also relates to the application of the GLP-1 analog dimer in the preparation of medicines for treating and / or preventing diabetes, obesity and Alzheimer's disease. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone synthesized primarily in L cells of the terminal jejunum, ileum, and colon and released into circulation in response to a meal. GLP-1(7-36,7-37), the major active form of GLP-1 in the systemic circulation, controls blood glucose through complex mechanisms including secretion of insulin and glucagon, gastric emptying, and regulation of peripheral insulin. The hypoglycemic effect of GLP-1(7-36,7-37) is glucose-dependent, can avoid hypoglycemia, and has the effect of inhibiting the apoptosis of islet β-cells and promoting the proliferatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/36C07K1/30C07K1/16C07K1/06C07K1/04A61K38/26A61P3/10A61P3/04A61P25/28
CPCA61K38/00C07K14/605Y02P20/55
Inventor 赵娜夏韩英梅王玉丽夏广萍
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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