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Novel exenatide analogue and use thereof

A technology of exenatide and analogues, applied in the field of new exenatide analogues, can solve the problems of excessive reagents and materials, short half-life, many reaction steps, etc., and achieve excellent hypoglycemia, continuous hypoglycemia, prevention or the effect of treating diabetes

Active Publication Date: 2017-05-10
安尼根有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] And, in the synthetic process of exenatide, there is the shortcoming that needs excessive reagent and material cost
Moreover, due to the many reaction steps, it is necessary to free intermediates according to different steps, and there is the possibility of isomers, so it is not easy to purify
[0006] As described above, there is a problem of needing to improve the disadvantages of the conventional exenatide in that it needs to be administered twice a day due to the short half-life of exenatide and has expensive preparation ingredients.

Method used

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  • Novel exenatide analogue and use thereof
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  • Novel exenatide analogue and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Embodiment 1: the preparation method of Ex4(1-32) K-Cap

[0130] The Ex4(1-32) K-Cap of the present invention comprises a lysine-fatty acid (Lysine-fatty acid) added to the sequence of serine at the 32nd position from the N-terminal of exenatide of the following chemical formula I A peptide of 33 amino acids.

[0131] Chemical formula Ⅰ:

[0132] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser

[0133] In order to prepare Ex4 (1-32) K-Cap of the present invention, Fmoc-Lys (dde) and dimethylformamide (DMF, Dimethylformamide) are accumulated in trityl resin (trityl resin) to prepare Fmoc-Ser (tBu )-trityl resin. Added N,N-dimethylformamide (N,N-Dimethylformamide; DMF) containing 20% ​​piperidine to the above Fmoc-Ser(tBu)-trityl resin and containing Fmoc-Pro-OH and hydroxybenzene N, N-dimethylformamide of triazole (HOBt, hydroxy-benzotriazole) to prepare Fmoc...

Embodiment 2

[0148] Example 2: Preparation and Effect Analysis of Short Exenatide-4 Analogs

[0149] Preparation of short exenatide-4 analogues and their stability tests against NEP24.11

[0150] The C-terminus of Exenatide-4 has a 9-AA C-terminal sequence (nine-AAC-terminal sequence) that Glucagon-like Peptide-1 does not have, so it is not easy to decompose into neutral peptides such as NEP24.11 Neutral endopeptidase (reference: Doyle ME et al., Regulatory Peptides Volume 114, Issues 2-3, 15 July 2003, Pages 153-158).

[0151] In order to test the stability of NEP24.11, which is a peptidase, the sequence of the C-terminus of the conventional exendin-4 was changed, and various short exendin-4 (short -exenatide-4) analogs.

[0152] (a) Preparation method of Ex4(1-29)

[0153] To prepare Ex4(1-29), accumulate Fmoc-Gly-OH, N,N-diisopropylethylamine (DIEA, N,N-Diisopropylethylamine) and dimethylformamide in trityl resin to prepare Fmoc -Gly-trityl resin. Add N,N-dimethylformamide containi...

Embodiment 3

[0197] Embodiment 3: the characteristic analysis of Ex4 (1-32) K (Cap)

[0198] Ex4(1-32)K(Cap)(subcutaneous) glucose tolerance test using diabetic model mice

[0199] After making male db / db mice (6-week-old to 12-week-old) fast for 18 hours, feed them to fasting mice at concentrations of 0.005 nmol / kg, 0.01 nmol / kg, 0.1 nmol / kg, 1 nmol / kg and 5 nmol / kg, respectively. The diabetic model mice were administered (subcutaneously) short exenatide-fatty acid conjugated Ex4(1-32)K(Cap), and 30 minutes later, glucose (1.5 g / kg) was intraperitoneally administered. After 0 minutes, 20 minutes, 40 minutes, 60 minutes, 90 minutes, 120 minutes, and 180 minutes, blood was collected from the tail end of the mice, and blood glucose was measured with a blood glucose meter. As a result, the concentration-dependent hypoglycemic effect of Ex4(1-32)K(Cap) was confirmed ( Figure 13a and Figure 13b ).

[0200] For comparison with Exenatide as a positive control group, Ex4(1-32)K(Cap) and Exen...

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PUM

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Abstract

The present invention relates to a novel exenatide analogue, which is an exenatide analogue in which the first to fifteenth amino acids from the C-terminal of the amino acid sequence of exenatide are deleted and a fatty acid is conjugated. The present invention provides a short length exenatide exhibiting almost the same level of anti-diabetic effects compared with that of conventional exenatide and liraglutide, which is an anti-diabetic drug, and capable of reducing the preparation cost of exenatide.

Description

technical field [0001] This patent application claims priority to Korean Patent Application No. 10-2014-0033712 filed with the Korean Patent Office on March 21, 2014, and the disclosures of the above patent application are incorporated herein by reference. [0002] The present invention relates to novel exenatide analogues and uses thereof. Background technique [0003] Exenatide as a functional analogue of glucagon-like peptide-1 (GLP-1) isolated from the salivary gland of the monster lizard (Heloderma suspectum) inhabiting the southwestern United States (analog), is used as type Ⅱ (Type Ⅱ) diabetes treatment agent. Exenatide, whose academic name is "Exendin-4 (Exendin-4)", is a physiologically active peptide composed of 39 amino acids and exists in the human body, but it is similar to glucagon-like peptide-1. Compared with, 53% of amino acids are similar, and stable to decomposing enzymes such as dipeptidyl peptidase-4 (DPP-4, Dipetidyl peptidase-4), therefore, compared ...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61P3/10
CPCA61K38/00A61K38/26A61K47/542A61K47/61A61P3/06A61P3/10C07K14/605A61P3/04A61P3/08A61K9/0053
Inventor 金载一金山淏金善明朴文英
Owner 安尼根有限公司
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