Exenatide modified compound and uses thereof

A technology of exenatide and modification, applied in the field of therapeutic peptides, can solve the problems of short duration of hypoglycemia, poor clinical use effect, frequent injection, etc., and achieve long duration of hypoglycemia, long action time and stability Good results

Active Publication Date: 2017-04-05
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to overcome the shortcomings of the currently disclosed exenatid

Method used

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  • Exenatide modified compound and uses thereof
  • Exenatide modified compound and uses thereof
  • Exenatide modified compound and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Exendin-4(1-39)-Cys(40)-NH 2 preparation of

[0044] .

[0045] Amino acid and its abbreviation and English abbreviation:

[0046]

[0047] The solid-phase peptide synthesis of the target peptide adopts the Fmoc method solid-phase synthesis, uses Fmoc-Rink MBHA Amide resin, uses 20% piperidine / DMF to remove Fmoc, uses HOBT / DIC as the coupling reagent, DMF as the reaction solvent, and uses Ninhydrin assay, sequentially attach the following protected amino acids to Rink MBHA Amide resin: Fmoc-Cys(Trt)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc -Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly -OH, Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile-OH , Fmoc-Phe-OH, Fmoc-Leu-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OtBu)- OH, Fmoc-Glu(OtBu)-OH, Fmoc-Met-OH, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ser(tBu)-OH, ...

Embodiment 2

[0049] Example 2 Preparation of Compound 1

[0050]

[0051] Preparation of BP103a01

[0052] Under nitrogen protection, add 200 mL pyridine and 120 g BP103a00 (1.0eq) to a 1000ml three-neck flask, stir to cool down to 0°C, add 151.8g TsCl (1.0eq) in batches, stir for 1h, then slowly rise to room temperature, and continue stirring 3-4h. After the reaction is over, pour the reaction solution into ice dilute hydrochloric acid solution, solids are produced, add EA for extraction, wash the EA layer with dilute hydrochloric acid once, wash with saturated sodium bicarbonate, and wash with saturated brine, then anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure to obtain 119 g of crude product, and 55 g of pure BP103a01 was obtained by silica gel column chromatography.

[0053] Preparation of BP103a02

[0054] Add 55 g BP103a01 (1.0eq) and 160 mL DMSO to a 1000 mL three-neck flask, stir well, then add NaN 3 23.52g (2.0 eq), heated to 50°C for...

Embodiment 3

[0064] Example 3 Preparation of Compound 2

[0065]

[0066] Step1

[0067] In a 250ml three-neck flask, add 150 mL pyridine and 50 g BP103g00 (1.0eq) under nitrogen protection, stir to cool down to 0°C, add 33.7g TsCl (1.0eq) in batches, stir for 1h, slowly warm up to room temperature, and stir for 3-4h. The completion of the reaction was monitored by TLC. The reaction solution was poured into ice dilute hydrochloric acid solution, extracted with EA, and the organic phases were combined. The EA layer was washed once with dilute hydrochloric acid, saturated sodium bicarbonate, saturated brine, and anhydrous Na 2 SO 4 Drying, spinning to obtain 59g, and column chromatography to obtain 31g of pure product BP103g01.

[0068] Step2

[0069] Add 33.5g BP103g01 (1.0eq), 100mL DMSO to a 250 mL three-neck flask, stir, add 10.0 g NaN 3 (2.0 eq), heated to 50 degrees and reacted for 3 hours and cooled to room temperature. TLC monitored the completion of the reaction. The reaction...

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Abstract

The invention discloses an exenatide modified compound, a use of the exenatide modified compound in preparation of a medicine which serves as a GLP-1 receptor stimulant, a use of the exenatide modified compound in preparation of medicines used for preventing and/or curing diseases and/or symptoms relevant to low GLP-1 receptor activity, a use of the exenatide modified compound in preparation of medicines used for diseases and/or symptoms relevant to carbohydrate metabolism, a use of the exenatide modified compound in preparation of medicines used for diabetes, a use of the exenatide modified compound in preparation of medicines used for fatty liver, and a use of the exenatide modified compound in preparation of medicines used for weight losing.

Description

technical field [0001] The invention relates to the field of therapeutic peptides, in particular to modified exenatide and its use, preparation method, pharmaceutical composition containing them and its use in treating diseases related to glucose metabolism. Background technique [0002] Exenatide (also known as Exenatide or Exendin-4, trade name Byetta) is a polypeptide composed of 39 amino acids with a molecular weight of 4186.6 and a molecular formula of C 184 h 282 N 50 o 60 S, the amino acid sequence is: His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu [0003] -Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 ; manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide was approved for marketing by the FDA in April 2005. It is a subcutaneous injection preparation that can promote glucose-dependent insulin secretion, restore first-phase insulin secretion, inhibit glucagon s...

Claims

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Application Information

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IPC IPC(8): C07K14/575A61K38/22A61P3/10A61P1/16A61P3/04
CPCA61K38/00C07K14/57563
Inventor 袁建栋黄仰青宋云松袁芳
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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