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A preparation method and application of side chain modified long-acting glp-1 analogs

A side chain modification, GLP-1 technology, applied in chemical instruments and methods, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as inconvenient clinical use, short half-life, and failure to meet clinical standards

Active Publication Date: 2018-02-09
天津天诚新药评价有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the serum half-life of GLP-1(7-37) is only 3-5 minutes, and multiple injections per day are very inconvenient in clinical use
[0003] At present, many studies have adopted GLP-1 analog fusion protein technology to solve the retention time of GLP-1 analog in vivo (CN90101167.3, CN200710018734.2, CN200410054397.9, CN01820232.2, CN200380110152.7, CN200510039265.3 , CN200610127237.1, CN200910009642.7), however, there is still a long way between the existing technology and the ideal clinical goal, and generally have not reached the clinical standard. Recently, Liraglutide produced by Novo Norisk is a GLP-1 analog , which modified GLP-1 with palmitic acid, and was launched in the United States in 2009
However, liraglutide also has the problem of short half-life, and its dosage form still needs daily injections
[0004]Therefore, there is currently a need for methods that address the short in vivo half-life of GLP-1

Method used

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  • A preparation method and application of side chain modified long-acting glp-1 analogs
  • A preparation method and application of side chain modified long-acting glp-1 analogs
  • A preparation method and application of side chain modified long-acting glp-1 analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Embodiment 1: the solid-phase synthesis of polypeptide

[0131] Using the solid-phase polypeptide synthesis method of the Fmoc strategy, the CS 336X instrument produced by CSBio Company was used to synthesize the polypeptide of the present invention. The method of synthesis was carried out according to the manufacturer's instruction manual.

[0132] The prepared polypeptide was purified using HPLC C18 semi-preparative column, and the mobile phase was acetonitrile. The polypeptide freeze-dried powder is obtained by desalting and freeze-drying.

Embodiment 2

[0133] Example 2: The hypoglycemic function related to GLP-1 analogs (general formula I)

[0134] In this embodiment, the polypeptides used are as follows:

[0135] SEQ ID NO1: 7HAEGT FTSDV SSYLE GQAAK(GGGGG) EFIAW LVKGR G 37 ;

[0136] SEQ ID NO2: 7 HAEGT FTSDV SSYLE GQAAK(GGGGG G) EFIAW LVKGR G 37 ;

[0137] SEQ ID NO3: 7 HAEGT FTSDV SSYLE GQAAK(GGGGG GG) EFIAW LVKGR G 37 ;

[0138] SEQ ID NO4: 7 HAEGT FTSDV SSYLE GQAAK(GGGGG GGG) EFIAW LVKGR G 37 ;

[0139] SEQ ID NO5: 7 HAEGT FTSDV SSYLE GQAAK(AAAAA) EFIAW LVKGR G 37 ;

[0140] SEQ ID NO6: 7 HAEGT FTSDV SSYLE GQAAK(AAAAA A)EFIAW LVKGR G 37 ;

[0141] SEQ ID NO7: 7 HAEGT FTSDV SSYLE GQAAK(AAAAA AA)EFIAW LVKGR G 37 ;

[0142] SEQ ID NO8: 7 HAEGT FTSDV SSYLE GQAAK(AAAAA AAA) EFIAW LVKGR G 37 ;

[0143] SEQ ID NO9: 7 HAEGT FTSDV SSYLE GQAAK(VVVVV) EFIAW LVKGR G 37 ;

[0144] SEQ ID NO10: 7 HAEGT FTSDV SSYLE GQAAK(VVVVV V) EFIAW LVKGR G 37 ;

[0145] SEQ ID NO11: 7 HAEGT FTSDV SSYLE GQAAK(VVVVV VV...

Embodiment 3

[0148] Example 3: Hypoglycemic function associated with GLP-1 analogs (formula II).

[0149] In this embodiment, the polypeptides used are as follows:

[0150] SEQ ID NO13: 7 HAEGT FTSDV SSYLE K(GGGGG)QAAK EFIAW LVKGR G 37 ;

[0151] SEQ ID NO14: 7 HAEGT FTSDV SSYLE K(GGGGG G)QAAK EFIAW LVKGR G 37 ;

[0152] SEQ ID NO15: 7 HAEGT FTSDV SSYLE K(GGGGG GG) QAAK EFIAW LVKGR G 37 ;

[0153] SEQ ID NO16: 7 HAEGT FTSDV SSYLE K(GGGGG GGG) QAAK EFIAW LVKGR G 37 ;

[0154] SEQ ID NO17: 7 HAEGT FTSDV SSYLE K(AAAAA)QAAK EFIAW LVKGR G 37 ;

[0155] SEQ ID NO18: 7 HAEGT FTSDV SSYLE K(AAAAA A)QAAK EFIAW LVKGR G 37 ;

[0156] SEQ ID NO19: 7 HAEGT FTSDV SSYLE K(AAAAA AA)QAAK EFIAW LVKGR G 37 ;

[0157] SEQ ID NO20: 7 HAEGT FTSDV SSYLE K(AAAAA AAA)QAAK EFIAW LVKGR G 37 ;

[0158] SEQ ID NO21: 7 HAEGT FTSDV SSYLE K(VVVVV)QAAK EFIAW LVKGR G 37 ;

[0159] SEQ ID NO22: 7 HAEGT FTSDV SSYLE K(VVVVV V)QAAK EFIAW LVKGR G 37 ;

[0160] SEQ ID NO23: 7 HAEGT FTSDV SSYLE K(VVV...

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Abstract

GLP-1 analogues are disclosed. The general formula A of the GLP-1 analogues is shown as follows: <7>HAEGT FX<13>SDV SSY X<20>E X<22>QAA X<26>EFIAW LVKGR G<37>. In the general formula A, the X<13> is threonine or side-chain-modified lysine (K-nX), the X<20> is leucine or the side-chain-modified lysine (K-nX), the X<22> is glycine or the side-chain-modified lysine (K-nX), the X<26> is lysine (K-NH2) free of side chain modification or the side-chain-modified lysine (K-nX), just only one of the X<13>, the X<20>, the X<22> and the X<26> is the lysine (K-nX), the n is 4-10, and the X is the glycine, alanine or valine. The GLP-1 analogues effectively prolong the blood half-life period of GLP-1, overcome the current situation that the GLP-1 cannot be used in clinic due to the short half-life period of the GLP-1, and have an application prospect in the field of medicines treating diabetes and obesity. A preparing method of the GLP-1 analogues and applications of the GLP-1 analogues are also disclosed.

Description

technical field [0001] The present invention relates to the field of drugs related to diabetes, in particular, the present invention relates to a GLP-1 analogue with a side chain half-life of glucagon-like peptide-1 (GLP-1) in vivo. The present invention also relates to the preparation method of the GLP-1 analog and its application in the preparation of diabetes drugs. Background technique [0002] GLP-1 (glucagon-likepeptide-1, hereinafter referred to as: GLP-1) involved in the present invention is a polypeptide composed of 37 amino acids mainly secreted by small intestinal L cells, and its active form is GLP-1(7-37) OH and GLP-1(7-36)NH2 (Mojsov S, J Clin Invest. 1987 Feb;79(2):616-9). GLP-1 significantly reduces blood sugar after meals, can stimulate the production of insulin, and can also achieve a certain weight loss effect, and will not cause hypoglycemia (Drucker D J, Diabetes.1998Feb; 47(2): 159-69) . Recent studies have also shown that GLP-1 has a role in pancrea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04
CPCA61K38/00C07K14/605
Inventor 孔维苓郑学敏王玉丽徐为人汤立达龚珉
Owner 天津天诚新药评价有限公司
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