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Insulinotropic peptide derivative wherein its n-terminal amino acid is modified

一种促胰岛素、释放肽的技术，应用在胰岛素样生长因子、激素肽、胰高血糖素等方向，能够解决未得到详细说明书的支持、没有提到类似物活性和性质等问题

Inactive Publication Date: 2010-07-14
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, the activity and properties of said analogues are not mentioned, nor are they supported by detailed descriptions

Method used

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  • Insulinotropic peptide derivative wherein its n-terminal amino acid is modified
  • Insulinotropic peptide derivative wherein its n-terminal amino acid is modified
  • Insulinotropic peptide derivative wherein its n-terminal amino acid is modified

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1. Plasma Stability of Exendin-4 Derivatives

[0057] To determine the plasma stability of exendin-4 derivatives, each of native exendin-4 and exendin-4 derivatives was exposed to plasma and the undenatured exendin-4 derivatives were determined by reversed-phase HPLC. The amount of protein remaining for denaturation testing dependent on exposure time.

[0058] In this experiment, for the analysis of plasma-exposed samples, the pooled plasma samples were deproteinized prior to analysis.

[0059] Natural exendin-4, deamino-histidyl-exendin-4 (DA-exendin-4), β-hydroxyimidazopropionyl-exendin- 4(HY-Exendin-4), β-Carboxyimidazopropionyl-Exendin-4(CX-Exendin-4), Dimethyl-Histidyl-Exendin Exendin-4 (DM-exendin-4) and imidazoacetyl-exendin-4 (CA-exendin-4) were prepared at a concentration of 1 mg / ml, respectively. Take 200 μl of each exendin-4 derivative sample and mix with 200 μl rat serum, and react at 37°C. At each sampling time, each sample is 0 hour, 1 hour, 2 h...

Embodiment 2

[0063] Example 2. Measuring the In Vitro Activity of Exendin-4 Derivatives

[0064] To determine the potency of exendin-4 derivatives including desamino-histidyl-exendin-4, their in vitro cell viability was tested. Natural exendin-4 and exendin-4 derivatives were synthesized by American Peptide Corporation. Insulinoma cells or islets, which are commonly used to measure GLP-1 activity in vitro, were isolated and analyzed for changes in cAMP production following GLP-1 treatment.

[0065] In this experiment, in vitro activity was measured using RIN-m5F (ATCC CRL-11605), which is known to be a rat insulinoma cell and has a GLP-1 receptor (and thus is commonly used to measure GLP-1 in vitro activity). RIN was treated with different concentrations of GLP-1, native exendin-4, and exendin-4 derivatives including N-terminal-α-deamino-histidyl-exendin-4 - m5F cells, measure cAMP production due to test material to determine EC 50 value.

[0066] Table 1

[0067] test materi...

Embodiment 3

[0068] Example 3. Measuring the insulin-releasing activity of exendin-4 derivatives

[0069] The insulinotropic activity of exendin-4 derivatives was compared in RINm5F cells. Thaw RINm5F cells, subculture at least once, and then in 1x10 5 Densities of cells / well were seeded into 96-well plates with medium containing FBS (Gibco, #11082). Then in 5% CO 2 Cells were incubated for 48 hours at 37°C in an incubator. The medium was replaced with fresh medium containing 0.5% FBS, followed by incubation for 1 hour. Each of CA-exendin-4 and exendin-4 (byetta, Amylin) was diluted with a medium containing 0.5% FBS and glucose to obtain a concentration of 10 nM to 0.001 nM. In addition to exendin samples, diluted solutions were prepared and used as controls. Remove the culture medium of RINm5F cells, add the prepared samples, and then in 5% CO 2 Incubate at 37°C for 1 hour in an incubator. Then, the medium in each well was recovered. Measure the insulin concentration in the recove...

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PUM

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Abstract

The present invention relates to an N-terminal amino acid-modified insulinotropic peptide having a high activity, and to a pharmaceutical composition comprising the same. The insulinotropic peptide derivatives according to the present invention exhibit therapeutic effects, which are not observed in native and other insulinotropic peptide analogs. Therefore, the insulinotropic peptide derivatives and the pharmaceutical composition comprising the same according to the present invention can be effectively provided for the treatment of the diseases.

Description

[technical field] [0001] The present invention relates to an insulinotropic peptide derivative having improved insulinotropic activity. In particular, the present invention relates to an N-terminal amino acid modified insulinotropic peptide having high stability and insulinotropic activity. [Background technique] [0002] Due to the low stability of the peptide, it is degraded by proteolytic enzymes in the body, it is easily denatured and thus loses activity, and it has a relatively small size, so it easily passes through the kidneys. Therefore, in order to maintain the blood level and titer of a drug containing a peptide as an active ingredient of the drug, it is necessary to frequently administer the peptide drug to a patient in order to maintain the desired blood level and titer. However, peptide drugs are usually administered in the form of injectable preparations, and frequent administration to maintain blood levels of physiologically active peptides causes severe pain...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/65
CPCC07K14/57563C07K14/605C07K14/46C07K14/575A61K38/00A61P43/00A61P3/10C07K14/65C07K14/00A61K38/26
Inventor 郑圣烨林昌基宋大海裵城敏金永勋权世昌李宽淳
Owner HANMI SCI CO LTD
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