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Bi-functional antiplatelet aggregation medicine and application thereof

An anti-platelet aggregation, dual-function technology, applied in the field of medicine, can solve problems such as no

Inactive Publication Date: 2014-04-02
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, there is no information about having P2Y at the same time 12 Drugs with Dual Functions of Receptor Antagonism and Phosphodiesterase Inhibition

Method used

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  • Bi-functional antiplatelet aggregation medicine and application thereof
  • Bi-functional antiplatelet aggregation medicine and application thereof
  • Bi-functional antiplatelet aggregation medicine and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1. Inhibition of Phosphodiesterase Activity by BF061

[0020] The purpose of this example is to demonstrate the anti-phosphodiesterase activity of BF061.

[0021] In this example, phosphodiesterase was purified from human platelets, and the enzyme reaction was performed in 200 μL of PBS buffer (137 mM NaCl, 2.7 mM KCl, 8.8 mM NaCl 2 HPO 4 , 1.5 mM KH 2 PO 4 , 1 mM CaCl 2 , 1 mM MgCl 2 , 10 μM cAMP, pH 7.4), the substrate is 25 μM cAMP (sigma company), the system contains 10 μL of phosphodiesterase, and the phosphodiesterase is calculated by measuring the residual substrate concentration after 30 minutes of enzyme reaction activity. The residual substrate concentration was determined by high-pressure liquid chromatography with a C18 column (Kromasil 4.6 × 150 mm, Eka-chemicals, Bohns, Sweden). The results are shown in Table 1, showing that BF061 has obvious inhibitory effect on phosphodiesterase activity.

[0022] Table 1: BF061 inhibits phosphodiestera...

Embodiment 2

[0024] Example 2. P2Y of BF061 12 receptor antagonism

[0025] The purpose of this example is to prove that BF061 has P2Y 12 Receptor antagonism.

[0026] In this example, the ligands ADP and P2Y 12 The binding force between the receptors was determined by atomic force microscopy (Asylum Research, Santa Barbara, CA). The probe was pre-coated in ADP (500 ng / μL, 20 μL) overnight, and finally ADP was coupled to the probe. P2Y 12 The receptor was expressed in CHO-K1 cells, and the conditions for the determination of the binding force between the probe and the cell surface receptor were: pressure velocity 3 μm / s, contact time 0.2 s, contact force 100 pN, cantilever correction coefficient about 20 pN / nm. The results are shown in Table 2. After BF061 treatment, the ligands ADP and P2Y 12 The binding force between receptors is significantly weakened, showing that BF061 has obvious P2Y 12 Receptor antagonism.

[0027] Table 2: BF061 antagonizes P2Y 12 Receptors bind to ...

Embodiment 3

[0029] Example 3. Inhibitory effect of BF061 on ADP-induced human platelet aggregation

[0030] The purpose of this example is to prove that BF061 can inhibit ADP-induced human platelet aggregation

[0031] Preparation of platelets: Platelets were obtained from healthy volunteers who signed the informed consent form. Volunteers had not taken any antiplatelet drugs such as aspirin and clopidogrel within 20 days before blood collection. Anticoagulant ACD (85 mmol L -1 sodium citrate, 71.38 mmol L -1 citric acid, and 27.78 mmol L -1 glucose). Centrifuge at 300 x g for 20 minutes to obtain platelet-rich plasma, take the supernatant and centrifuge at 900 x g for 10 minutes to obtain platelets, and finally resuspend in Tyrode’s buffer (138 mmol L -1 NaCl, 2.7 mmol L -1 KCl, 2 mmol L -1 MgCl 2 , 0.42 mmol L -1 NaH 2 PO 4 , 5 mmol L -1 glucose, 10 mmol L -1 HEPES, 0.2% bovine serum albumin, and 0.02 unit mL -1 apyrase, pH 7.4), to obtain washed platelets, the nu...

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Abstract

The present invention belongs to the technical field of pharmaceuticals. Disclosed are a bifunctional anti-platelet aggregation medicament represented by formula (I) and its uses for preventing and treating arterial thrombotic diseases. The medicament of the present invention has P2Y12 receptor-antagonist activity and phosphodiesterase-inhibiting activity at the same time. The anti-platelet mechanism of the medicament is provided by the experimental results of anti-platelet aggregation activity in vivo and in vitro. The structure and anti-platelet mechanism of the medicament are different from known anti-platelet medicaments Aspirin, Clopidogrel, Prasugrel, Cilostazol and platelet fibrinogen receptor antagonist. The medicament of the present invention shows good inhibiting effects on platelet aggregation induced by many kinds of agonists. The experimental results of the arterial thrombotic model of mice in vivo shows that the medicament has excellent anti-thrombus activity similar to Clopidogrel without any obvious side-effect of bleeding. The medicament of the present invention can be used as anti-thrombus medicines for treating arterial thrombotic diseases such as coronary heart disease, stroke, and so on. Said formula (I) is as follows.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to an antiplatelet medicine and its application in preventing and treating arterial thrombosis diseases. Background technique [0002] With the improvement of living standards, stroke, coronary heart disease and other arterial thrombotic diseases have become the number one killer threatening the health of people in our country and developed countries. Studies have shown that intravascular thrombus formation caused by abnormal activation of platelets is the pathological basis of arterial thrombosis coronary heart disease and stroke, so antiplatelet drugs that inhibit platelet activation have become the main means of prevention and treatment of such diseases. Relevant studies have shown that the curative effect of antiplatelet drugs on coronary heart disease and stroke is affirmative, but practice shows that the therapeutic effect of coronary heart disease and stroke is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/167A61K31/7076A61P7/02A61P9/10
CPCA61K31/7076C07H19/167A61P7/02A61P9/10
Inventor 丁忠仁胡亮张思杜洪光
Owner FUDAN UNIV
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