Secretin analogue, as well as preparation method and application thereof

An analog, secretin technology, applied in the direction of insulin, hormone peptides, biological testing, etc., can solve the problems of reduced biological activity, instability of natural secretin, increased transportation and storage costs, etc., to achieve improved chemical stability, The effect of reducing degradation, increasing the degree of α-helix

Active Publication Date: 2013-06-26
泰德医药(浙江)股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] During the preparation process, storage and transportation of natural secretin, its instability will lead to the reduction of biological activity, which cannot meet the safety and effectiveness in diagnosis and treatment.
Moreover, due to the instability of natural secretin, the cost of transportation and storage will inevitably increase, which indirectly leads to the increase of drug costs.

Method used

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  • Secretin analogue, as well as preparation method and application thereof
  • Secretin analogue, as well as preparation method and application thereof
  • Secretin analogue, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of embodiment 1 secretin analog

[0040] according to figure 1 In the steps shown, the amino acids are attached to the resin one by one, and then a catalyst is used to catalyze the ring closure, and then the protecting group is removed and the polypeptide is cleaved from the resin.

[0041] 1. Solid phase synthesis

[0042] Select 0.402g Rink amide linker MBHA resin (substitution degree: 0.373mmol / g) to prepare, soak the resin with DMF at room temperature for 60min, arrange the amino acids with Fmoc protection in the synthesizer according to the order of the sequence, and perform activation linking to obtain Compounds as shown.

[0043]

[0044] 2. Catalytic cyclization

[0045] The compound 2 obtained in the above steps was washed twice with DCM (20ml) and DCE (20ml) respectively, then soaked with DCE (8ml) for 30min, and then Grubbs 1 st (25mgx2, 20mg / 0.1mmol) was added to the reaction mixture and shaken at room temperature for 3 hours. The cyc...

Embodiment 2

[0051] The in vitro stability test of embodiment 2 secretin analogs

[0052] The natural secretin secretin analogs of the present invention (prepared in Example 1) were placed in 0.1M phosphate buffer (pH7.0), placed at 60°C for 36 hours, and detected by RP-HPLC every three hours Wherein the residual amount of secretin or similar.

[0053] Take samples of secretin and analogues with CH 3 CN and 1% HClO 4 (2:3, v / v) dilution, C 18 The column is the stationary phase, acetonitrile / 0.005M phosphate buffer / 0.2MNaClO 4 It is the mobile phase and detected at 210nm.

[0054] The result is as figure 2 As shown, under the experimental conditions, natural secretin is rapidly degraded, about 30% degraded in 24 hours; while the analogue of the present invention hardly degrades.

Embodiment 3

[0055] The in vitro biological experiment of embodiment 3 secretin analogs

[0056] Ten Wistar rats with a body weight of 200±20 g were selected and randomly divided into two groups (natural secretin group and analog group). Rats were anesthetized with urethane (45 mg / kg), the abdominal cavity was cut open, the pancreas was peeled off, and the isolated pancreas was quickly placed in a constant temperature incubator containing Krebs-Ringer buffer (KR solution) at 37°C. Fill PH7.2 with 95% O with a constant flow pump 2 and 5% CO 2 The KR solution was poured into the abdominal aorta at a constant rate (1.0ml / min), and the buffer solution in the incubation dish was continuously supplied at a rate of 0.35ml / min. The two groups were perfused with 0.25CU / kg.h of natural secretin and the analogue of the present invention (Example 1). A microcapillary was inserted into the pancreatic duct, and the pancreatic juice flowed out along the capillary. The pancreatic juice was collected ev...

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Abstract

The invention relates to a novel secretin analogue and a preparation method of the novel secretin analogue. Compared with natural secretin, the compound has improved chemical stability and maintains the pharmacological activity of the natural secretin.

Description

technical field [0001] The present invention relates to secretin analogues and their preparation methods and therapeutic uses. Background technique [0002] Secretin is a gut hormone that is formed in the upper mucosa of the small intestine and stimulates the pancreas to secrete water and bicarbonate. Secretin is a 27-amino acid linked polypeptide. [0003] Human secretin is a polypeptide compound with the following sequence: [0004] h 2 N-His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln- Gly-Leu-Val-CONH 2 [0005] Secretin can stimulate and promote the secretion of weak alkaline enzyme-containing pancreatic juice from the pancreas. It is a commonly used reagent for diagnosing pancreatic function. Studies have shown that secretin also has the effect of treating peptic ulcer. US2004241154 discloses the use of secretin in the treatment of asthma. WO2004081195 discloses the use of secretin to treat infectious diseases. US...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/62G01N33/74A61K38/28A61P1/04
Inventor 李湘
Owner 泰德医药(浙江)股份有限公司
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