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Novel Exenatide Analogs and Their Uses

A technology of exenatide and analogs, applied in the field of new exenatide analogs, can solve the problems of excessive reagents and materials, many reaction steps, short half-life, etc., to achieve excellent blood sugar reduction, prevention or treatment of diabetes, Sustained blood sugar lowering effect

Active Publication Date: 2021-03-16
安尼根有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 Analogs and Their Uses
  • Novel Exenatide Analogs and Their Uses
  • Novel Exenatide Analogs and Their Uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] [Example 1: 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-Gly-...

Embodiment 2

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

[0149] [Preparation of short exenatide-4 analogues and stability test 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 containin...

Embodiment 3

[0197] [Example 3: 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 Exenatide...

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Abstract

The present invention relates to new exenatide analogues and uses thereof, the exenatide analogues are deleted from 1 to 15 amino acids at the C-terminal of the amino acid sequence of exenatide, and are combined with fatty acids Exenatide analogs for conjugation. Compared with conventional exenatide and liraglutide as an antidiabetic drug, the present invention exhibits almost the same level of antidiabetic effect, and provides a short-length exenatide that can save the production cost of exenatide peptide.

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