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GLP-1R/GCGR/GIPR triple receptor agonist and application thereof

A parent, ac-his technology, applied in the GLP-1R/GCGR/GIPR triple receptor agonist and its application field, can solve problems such as increasing satiety, raising blood sugar and accelerating insulin resistance, achieving good hypoglycemic and promoting Effects of islet secretion, improvement of tolerance, and reduction of degradation rate

Active Publication Date: 2022-05-06
深圳深创生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The characteristics of glucagon to increase satiety and promote energy expenditure make it a potential therapeutic target for obesity, but its effects of raising blood sugar and accelerating insulin resistance limit its application

Method used

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  • GLP-1R/GCGR/GIPR triple receptor agonist and application thereof
  • GLP-1R/GCGR/GIPR triple receptor agonist and application thereof
  • GLP-1R/GCGR/GIPR triple receptor agonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1: Preparation of linear peptide resin for analog1-analog9

[0124] Weigh 62.5 g (20 mmol) of Fmoc-Rink-Amide resin (Sub=0.32 mmol / g) into the reaction column, wash with DMF for 3 times, and then swell with DMF for 30 minutes. The Fmoc protecting group was then removed with DBLK, followed by 6 washes with DMF. Weigh 18.66 g (60 mmol) of Fmoc-Ala-OH and 8.91 g (66 mmol) of HOBt, dissolve them in DMF, add 11.35 g of DIC (90 mmol) in an ice-water bath at 0°C, activate for 5 minutes, add to the reaction column, and react for 2 hours , and then remove the Fmoc protecting group with DBLK. Repeat the above operation, and couple Fmoc-Ile-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc- Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys( Alloc)-OH or Fmoc-Dap(Alloc)-...

Embodiment 2

[0125] Example 2: Removal of the side chain protecting group Alloc of analog1-analog9

[0126] The fully protected peptide resin obtained in Example 1 was washed 3 times with DCM. Weigh 43.2 grams of phenylsilane, measure 500ml of DCM, add to the reaction column, after reacting for 5 minutes, add 11.55 grams of Pd 0(Ph 3 P) 4 , reacted for 1 hour. Then the resin was washed 3 times with DCM, the peptide resin was washed with DMF solution for 30 minutes, the resin was washed with DMF for 3 times, and then the resin was washed with DCM for 3 times to obtain a peptide resin from which Alloc was selectively removed, which was set aside.

[0127] The resulting resin was divided into 10 fractions, 2 mmol each, for the synthesis of analog1 to analog9.

Embodiment 3

[0128] Example 3: Coupling of analog1 side chains

[0129] Weigh 2.31 g (6 mmol) of Fmoc-AEEA-OH, 0.89 g (6.6 mmol) of HOBt, dissolve in DMF, add 1.13 g of DIC (9 mmol) in an ice-water bath at 0°C, activate for 5 minutes, and add the Peptide resin, reacted for 2 hours, and then removed the Fmoc protecting group with DBLK. Repeat the above operation, and couple Fmoc-AEEA-OH, Fmoc-Glu-OtBu, and tert-butyl octadecanedioate in sequence; after the reaction, wash with DMF for 6 times and DCM for 3 times, then add methanol Wash 3 x 10 minutes, and vacuum dry to obtain 18.8 g of analog1 peptide resin.

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Abstract

The invention discloses a GLP-1R / GCGR / GIPR triple receptor agonist and application of the GLP-1R / GCGR / GIPR triple receptor agonist. The polypeptide compound provided by the invention has a parent peptide represented by the following amino acid sequence: H < X > a < 1 > < X > a < 2 > < Glu3-Gly4 < X > a < 5 >-Phe6 < X > a < 7 > < X > a < 8 >-Asp9 < Val < 10 > < X > a < 11 >-Ser12 < X > a < 13 > Leu14 < Glu15 < Gly16 < Gln < 17 >-X < aa < 18 >-Ala19 < X > a < 20 >-Glu21 < 1 >-Phe22 < Val < 27 >-X < aa < 18 >-Ala24 < Trp < 25 >-Leu26 < Val < 27 >-X < aa < 28 >-Gly29 < Arg < 30 >-Gly31 The polypeptide compound has the functions of reducing blood sugar, promoting insulin secretion, controlling appetite, regulating metabolic disorder, controlling lipolysis, improving heat consumption and the like, has the characteristics of good stability, high biological activity and the like, can be used as a GLP-1R / GCGR / GIPR triple receptor agonist, is expected to be used as a new-generation medicine for preventing or treating diabetes and obesity, and has wide application prospects. The traditional Chinese medicine composition can be used for preventing or treating diseases such as non-alcoholic fatty liver diseases, hyperlipidemia, arteriosclerosis and the like.

Description

technical field [0001] The present invention relates to a glucagon-like peptide-1 receptor (Glucagon-like Peptide-1 receptor, GLP-1R), glucose-dependent insulinotropic peptide receptor (Glucose-dependent Insulinotropic Peptide receptor, GIPR), glucagon Glucagon receptor (Glucagon receptor, GCGR) triple receptor agonist analog design and screening, specifically related to a GLP-1R / GCGR / GIPR triple receptor agonist and its application. Background technique [0002] Diabetes is a metabolic disease characterized by high blood sugar. At present, there are more than 465 million diabetic patients in the world, and it is expected to exceed 500 million by 2025. China has become the second largest country with diabetes after India, and type 2 diabetes accounts for about 90% of the total number of diabetic patients. Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by increased hepatic glucose output, defective pancreatic β-cell function, insufficient insul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P9/10A61P9/12A61P13/12A61P25/00A61P27/02
CPCC07K14/001A61P3/00A61P3/10A61P3/04A61P3/06A61P9/10A61P1/16A61P13/12A61P9/12A61P27/02A61P25/00A61K38/00
Inventor 王宇恩张凌云戴政清马亚平
Owner 深圳深创生物药业有限公司
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