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Cyclic peptide lhrh antagonist derivatives and their pharmaceutical use

A use and drug technology, applied in the field of secretory steroids, can solve the problems of difficult oral absorption of LHRH antagonist drugs, high histamine release, low bioavailability, etc., and achieve good antagonistic activity, high enzyme stability, and high enzyme. Effects of stability and lipophilicity

Inactive Publication Date: 2016-04-20
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although there are many LHRH antagonists developed at present, as a peptide drug, most of them still have the disadvantages of low bioavailability, short half-life in vivo, and high release of histamine.
Similar to other peptide drugs, LHRH antagonist drugs are also poorly absorbed orally
As far as we know, currently marketed LHRH antagonist drugs are administered by non-oral route

Method used

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  • Cyclic peptide lhrh antagonist derivatives and their pharmaceutical use
  • Cyclic peptide lhrh antagonist derivatives and their pharmaceutical use
  • Cyclic peptide lhrh antagonist derivatives and their pharmaceutical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Synthesis of Cyclic Peptide LHRH Antagonist Derivatives

[0079] Weigh 0.5g of MBHA resin into the reactor, add DCM (4-dicyanomethylene) to swell for 30min, and stir magnetically to disperse the resin evenly. Drain, wash with DCM, methanol (MeOH), DCM (3×2min) (the same below), and drain. Add 10% DIEA / DCM to neutralize (2×5min), release the amino group, wash the resin, and drain it. (1) Add 1.08mmol of Fmoc-D-Ala-OH, 1.08mmolHOBt, 1.08mmolDIC (N,N'-diisopropylcarbodiimide) in 2mLCH 3 OH, 4mL DCM at room temperature for 4h. (2) Wash, drain, and take a little resin to detect with ninhydrin indicator. Take a little resin in a small glass test tube, and add two drops of each of the three solutions of ninhydrin in turn. Heat at 110°C for 5min. Positive: Most of the resin is blue or light red, and the solution is blue; Negative: The resin is colorless and transparent, and the solution is light yellow. If positive, repeat 1. (3) If negative, sequentially coup...

Embodiment 2

[0087] Embodiment 2: In vivo testosterone inhibition experiment in rats

[0088] The body weight of the animals (SD male rats) was weighed before the experiment, and the blood was collected from the venous plexus behind the glass capillary bulb. 8, 16, and 24 hours after excessive subcutaneous injection or intragastric administration of the compound to be tested (different doses), blood was collected from the retrobulbar venous plexus, centrifuged at 5000 rpm for 8 minutes, and the separated serum was subjected to chemiluminescence (AccessImmunoassaySystem chemiluminescence instrument from Beckman Coulter, USA) Serum testosterone levels were measured. Please refer to Table 2 for specific results. It can be seen that the compound of the present invention can effectively inhibit the activity of testosterone in rats.

Embodiment 3

[0089] Example 3: Determination of Antagonistic Activity on GnRH (Gonadotropin-releasing Hormone) Receptor

[0090] The calcium ion-sensitive fluorescent dye is used to detect the function of GnRH receptor. When the GnRH receptor is activated by the agonist, it can trigger the release of calcium ion in the endoplasmic reticulum. The calcium ion can combine with the fluorescent dye to increase the fluorescence intensity. The stronger the fluorescence signal, the stronger the activity of the ligand or agonist, otherwise the weaker the activity of the ligand or agonist. Since the antagonistic compounds can competitively bind to the GnRH receptor, the release of calcium ions in the endoplasmic reticulum is reduced, and the fluorescence signal is also reduced. The inhibitory activity of the compound to be tested on the GnRH receptor is characterized according to the degree of signal reduction.

[0091] CHO-K1 / Gα15 cells (purchased from GenScript) stably expressing GnRH receptors w...

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Abstract

Disclosed in the present invention are cyclopeptide derivatives with LHRH acceptor antagonistic activity of general formula I, the preparation method thereof, the pharmaceutical composition containing them and uses thereof in the preparation of medicines for treating prostate cancer, endometrial cancer, ovarian cancer, breast cancer and other sexual hormone dependent diseases related to reproduction, and of contraceptives.

Description

technical field [0001] The present invention relates to cyclic peptide derivatives with luteinizing hormone-releasing hormone (LHRH) receptor antagonistic activity, which can inhibit pituitary secretion of gonadotropin and gonadal secretion of steroid hormones, its preparation method and pharmaceutical composition containing them And their use in the treatment of prostate cancer, endometrial cancer, ovarian cancer, breast cancer and other sex hormone-dependent diseases related to reproduction, contraception, etc. Background technique [0002] LHRH is also called GnRH (gonadotropin-releasing hormone), and its main physiological function is to regulate the level of sex hormones in the body. The LHRH in the body is mainly synthesized and secreted by the neurons of the hypothalamus (Hypothalamus), and is released to the pituitary (Pituitary) portal vein (Portalveins) at a pulse frequency of about once an hour. Two gonadotropins are secreted in the blood circulation, luteinizing...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06A61K38/08A61P5/24A61P15/18A61P35/00A61P13/08A61P15/00A61P15/08A61P5/00A61P5/28A61P5/32A61P5/36C07K1/06C07K1/04
CPCA61K38/00A61P5/00A61P5/08A61P5/24A61P5/28A61P5/32A61P5/36A61P13/08A61P15/00A61P15/08A61P15/18A61P35/00C07K7/23
Inventor 刘克良周宁李改桃吕玉健冯思良周文霞张永祥程军平郄建坤梁远军许笑宇王晨宏孟庆斌韩寒徐亮蔡俐锋
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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