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Long-acting GLP-1 (glucagon-like peptide-1) analogue dimer and medical application thereof

A technology of glucagon and analogues, which is applied in the application field of glucagon-like peptide-1 analogue dimers and medicines, can solve the problems such as medication compliance needs to be improved, and achieve the improvement of clinical application compliance , Avoid safety risks, hypoglycemic effect

Active Publication Date: 2017-10-20
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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  • Long-acting GLP-1 (glucagon-like peptide-1) analogue dimer and medical application thereof
  • Long-acting GLP-1 (glucagon-like peptide-1) analogue dimer and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] A. Preparation of GLP-1 analogue monomer:

[0064] 1) Synthesis: Fmoc method is adopted, and the step-by-step synthesis method is implemented according to the following steps:

[0065] a) Fmoc-arginine-resin is obtained by coupling an amino resin solid-phase support and Fmoc-protected arginine in the presence of an activator system;

[0066] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection; take the following protection measures for amino acids with side chains: use Boc (tert. Butoxycarbonyl), OtBu (oxygen-tert-butyl) for glutamic acid, Boc (tert-butoxycarbonyl) for lysine, Trt (trityl) for glutamine, tBu (tert-butyl) for tyrosine ), Trt (trityl) or tBu (tert-butyl) for serine, OtBu (oxygen-tert-butyl) for aspartic acid, tBu (tert-butyl) for threonine, and Trt (three-butyl) for histidine benzyl) or Boc (tert-bu...

Embodiment 2

[0079] A. Preparation of GLP-1 analogue monomer:

[0080] 1) Synthesis: Fmoc method is adopted, and the step-by-step synthesis method is implemented according to the following steps:

[0081] 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;

[0082] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection; take the following protection measures for amino acids with side chains: use Boc (tert. Butoxycarbonyl), OtBu (oxygen-tert-butyl) for glutamic acid, Boc (tert-butoxycarbonyl) for lysine, Trt (trityl) for glutamine, tBu (tert-butyl) for tyrosine ), Trt (trityl) or tBu (tert-butyl) for serine, OtBu (oxygen-tert-butyl) for aspartic acid, tBu (tert-butyl) for threonine, and Trt (three-butyl) for histidine benzyl) or Boc (tert-butoxyc...

Embodiment 3

[0095] A. Preparation of GLP-1 analogue monomer:

[0096] 1) Synthesis: Fmoc method is adopted, and the step-by-step synthesis method is implemented according to the following steps:

[0097] a) Fmoc-Ala-resin is obtained by coupling a resin solid phase support and Fmoc-protected alanine in the presence of an activator system;

[0098] b) Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal Fmoc-protection and side chain protection; take the following protection measures for amino acids with side chains: use Boc (tert. Butoxycarbonyl), OtBu (oxygen-tert-butyl) for glutamic acid, Boc (tert-butoxycarbonyl) for lysine, Trt (trityl) for glutamine, tBu (tert-butyl) for tyrosine ), Trt (trityl) or tBu (tert-butyl) for serine, OtBu (oxygen-tert-butyl) for aspartic acid, tBu (tert-butyl) for threonine, and Trt (three-butyl) for histidine benzyl) or Boc (tert-butoxycarbonyl)...

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Abstract

The invention belongs to the technical field of medicine and particularly provides a long-acting GLP-1 (glucagon-like peptide-1) analogue dimer. The dimer is formed by two GLP-1 analogue monomers which are represented as the general formula HAX1GTFTSDVSSYLEGQAAKEFIX2WLVK X3RZ, wherein Z is NH2, G, GNH2, -GCG or -GCA; X1 is Leu, Pro, Phe or Tyr; X2 is Ala or Cys; X3 is Gly or Aib; when X2 is Ala, Z is -GCG or -GCA; when X2 is Cys, Z is NH2, G or GNH2. The long-acting GLP-1 analogue dimer has a long-acting hypoglycemic effect and is highly homologous with endogenous GLP-1(7-37), thereby being capable of avoiding safety risks, and clinical medication compliance can be improved.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a glucagon-like peptide-1 (GLP-1) analog dimer with long-acting effect. 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 proliferation of...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P25/28
CPCA61K38/00C07K14/605
Inventor 赵娜夏韩英梅夏广萍王玉丽
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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