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Erythropoietin mimetic peptide chemical dimer and use thereof

An erythropoietin and peptide-mimicking technology, applied in erythropoietin, extracellular fluid diseases, chemical instruments and methods, etc., can solve problems such as poor in vivo stability and inability to meet the conditions for ready-made medicines

Active Publication Date: 2014-12-24
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the half effective concentration (EC 50 ) The smallest is 200nM, which is much higher than the EC of EPO measured at the same time 50 (20pM), in addition, their in vivo stability is also poor, therefore, can not meet the requirements of drug

Method used

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  • Erythropoietin mimetic peptide chemical dimer and use thereof
  • Erythropoietin mimetic peptide chemical dimer and use thereof
  • Erythropoietin mimetic peptide chemical dimer and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0127] Embodiment 2: the synthesis of SEQ-02

[0128]

[0129] a) Synthesis of N-tert-butoxyyl-β-alanyl-iminodiacetic acid hydroxysuccinimide ester (2a) become

[0130]

[0131] Put 4.03g (25mmol) of dimethyl iminodiacetate in a 250ml eggplant-shaped bottle, add 100ml of dry dichloromethane, add 4.7g (25mmol) of BOC-β-Ala-OH, and dissolve 4.1g (30mmol) of HOBt in 10ml of DMF Add the reaction bottle into the reaction bottle, stir under the ice bath, finally add 5.82g (30mmol) EDC, return to the temperature naturally, and stir overnight. Concentrate under reduced pressure, add ethyl acetate to dissolve the residue, in a separatory funnel, successively saturated NaCl, 10% HCl aqueous solution, saturated NaCl, saturated NaHCO 3 , saturated NaCl wash, organic layer anhydrous Na 2 SO 4 dry. After filtration and concentration to obtain an oily substance, the oil pump was drained to obtain 7.07 g of a foamy solid, with a yield of 84%.

[0132]Weigh 5g (15mmol) of the ...

experiment example 1

[0136] Biological experiment example 1: EPO receptor-mediated cell proliferation activity evaluation

[0137] The method for detecting EPO activity in vitro is mainly based on the study of EPO-induced proliferation and / or differentiation of EPO-sensitive cells. TF-1 cells (purchased from GenScript Corporation) are such cells. The TF-1 cell line was first isolated from human erythrocytic leukemia patients, and the cells highly express EPOR. The proliferation of TF-1 cells depends on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL-3). EPO can also induce the proliferation of TF-1 cells, and has been used as a generally accepted method for in vitro detection of EPO activity (T Kitamura, et al.Blood.1989, 73:375-380.S Chretien, et al.The EMBO J .1996, 15:4174-4181). The proliferative activity of EPO receptor-mediated erythropoietin mimetic peptide was determined at the cellular level. The results are shown in Table 1.

[0138] Table 1. Cell pr...

experiment example 2

[0141] Biological experiment example 2: evaluation of red blood cell activity in normal mice

[0142] Animals: mice (KM, male, 18-22g, Experimental Animal Center, Academy of Military Medical Sciences);

[0143] Drug preparation: the drug is ready-to-use, with 0.1% BSA saline as the vehicle.

[0144] Automatic blood analyzer (French YODER company).

[0145] Test method: Adult male mice were randomly divided into 5 groups, about 10 in each group. Animals were administered continuously for 7 days, 1 time / d, subcutaneous injection (sc), and blood was collected to measure various indicators at the end of the test (entrusted to 307 Hospital for testing). Use rhEPO (recombinant EPO, Huanerbo, 5000IU / mL, Sihuan Biopharmaceutical Co., Ltd.) as a positive control.

[0146] Experimental results: see Table 2.

[0147] Table 2 Effects of Compounds on the Production of Peripheral Red Blood Cells (RBC), Hemoglobin (Hb) and Reticulocytes (RET)

[0148]

[0149] Note: The vehicle is ...

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Abstract

The invention relates to an erythropoietin mimetic peptide chemical dimer and a use thereof. In particular, the invention relates to the erythropoietin mimetic peptide chemical dimer represented by the formula (I) or a pharmaceutically acceptable salt thereof, and a composition comprising the erythropoietin mimetic peptide chemical dimer or the pharmaceutically acceptable salt thereof. The invention further relates to the use of the erythropoietin mimetic peptide chemical dimer or the pharmaceutically acceptable salt thereof. The erythropoietin mimetic peptide chemical dimer or the pharmaceutically acceptable salt thereof has a better erythropoietic generating activity.

Description

technical field [0001] The present invention relates to erythropoietin mimetic peptide chemical dimer, its preparation method, pharmaceutical composition containing it, and the erythropoietin mimetic peptide chemical dimer in the prevention or treatment of erythropoietin or erythrocyte deficiency Use in diseases characterized by deficiency or deficiency. Background technique [0002] Erythropoietin (EPO) is a hematopoietic growth factor (HGF) and a glycoprotein necessary for red blood cell production. Containing 165 amino acids, the molecular weight is about 30.4kD, 40% of the molecular weight is the result of glycosylation modification, and the glycosylation sites are asparagine side chain amino N-glycosylation at positions 24, 38, and 83 and 126 Serine side chain hydroxyl O-glycosylation. In humans, EPO is mainly produced in the kidney and liver of the fetus, and is synthesized and released by the peritubular capillary endothelial cells of the renal tubules. As a cytoki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/505A61K38/18A61P7/06
CPCA61K38/00C07K14/505A61P7/06
Inventor 刘克良梁远军许笑宇颜玲娣董华进宫泽辉冯思良郄建坤贾启燕
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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