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Novel PAR-1 inhibitor and preparation method thereof

A PAR-1, inhibitor technology, applied in pharmaceutical formulations, medical preparations containing active ingredients, extracellular fluid diseases, etc., can solve problems such as low activity, achieve high activity, high safety, and easy industrialized mass production Effect

Active Publication Date: 2021-05-07
SHANDONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the above compound structure has the following problems: the activity is low, and its IC 50 Value reached only 23.83nM

Method used

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  • Novel PAR-1 inhibitor and preparation method thereof
  • Novel PAR-1 inhibitor and preparation method thereof
  • Novel PAR-1 inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation method of the described novel PAR-1 inhibitor (compound I), the concrete steps are as follows:

[0033] (1) Preparation of compound V

[0034] Weigh 8.40 g of sclareolide into a round-bottomed flask, add 143 mL of formic acid (99%) and 6 mL of concentrated sulfuric acid (93%) in turn, stir at room temperature for 3 h, then quench the reaction with ice water, extract with 200 mL of ether, The organic phase was sequentially washed with saturated sodium bicarbonate and saturated brine. The organic phase was dried by adding anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound II as a white solid. It was dissolved by adding 150 mL of tetrahydrofuran. Then, 50 mL of a 1 M solution of potassium hexamethyldisilazane in tetrahydrofuran and 5.6 mL of trimethoxyphosphorus were slowly added to the round-bottomed flask. Finally, oxygen was introduced to react at -78°C. After the reaction was completed, the system...

Embodiment 2

[0041] The preparation method of described novel PAR-1 inhibitor (compound I), concrete steps are as follows:

[0042] (1) Preparation of Compound V

[0043] Weigh 200g of sclareolide into a round bottom flask, add 3.4L of formic acid (99%) and 143mL of concentrated sulfuric acid (93%) successively, stir at room temperature for 3h, then quench the reaction with ice water, extract with 4.5L of ether , the organic phase was sequentially washed with saturated sodium bicarbonate and saturated brine, the organic phase was dried by adding anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain white solid compound II. 3.4 L of tetrahydrofuran was added to dissolve it. Then, 1.2 L of a 1M tetrahydrofuran solution of potassium hexamethyldisilazane and 134 mL of trimethoxyphosphine were slowly added to the round bottom flask in sequence. Finally, oxygen was introduced and reacted at -78°C. After the reaction was completed, the system was lower...

Embodiment 3

[0047] Determination of biological activity (PAR-1 inhibitory activity) of compounds

[0048] 1. Cell culture

[0049] 1.1 Cell Recovery

[0050] The HEK293-Gα15-PAR1 cell line (HDBiosciences stable cell line) was quickly taken out of the liquid nitrogen tank, and kept shaking in a 37°C water bath until it completely melted. The cell suspension was quickly added to the preheated medium (90% DMEM+10% FBS+1XPen / Strep), put into a centrifuge, and centrifuged at 1000 rpm for 10 minutes. Take out the centrifuge tube, discard the supernatant, add fresh preheated medium to the centrifuge tube, resuspend the cells, add the cell suspension to the culture dish, 37°C, 5% CO 2 nourish.

[0051] 1.2 Subculture

[0052] When the cells grow to 80-90% of the culture dish, gently wash the cells with 0.05% trypsin-EDTA, remove part of the digestion solution and incubate for 2-3 minutes, stop the digestion with a new medium, blow the cells gently with the tip of the pipette and Cells are re...

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Abstract

The invention belongs to the technical field of blood coagulation resistance, and particularly relates to a novel PAR-1 inhibitor and a preparation method thereof. The structural formula of the novel PAR-1 inhibitor is as follows: the novel PAR-1 inhibitor is prepared by taking a commercially available natural product sclareolide as a raw material through five-step reaction. The PAR-1 inhibitor has the advantages that the parent nucleus is highly similar to vorapaxar, the action target is clear, the structure is novel, the activity is high, the IC50 value of the PAR-1 inhibitor can reach the nanomole level, the safety is high, the preparation cost is low, the industrial batch production is easy, and the PAR-1 inhibitor has a very good application prospect as a candidate drug for treating thrombotic diseases.

Description

technical field [0001] The invention belongs to the technical field of blood anticoagulation, and in particular relates to a novel PAR-1 inhibitor and a preparation method thereof. Background technique [0002] According to the "China Cardiovascular Disease Report 2017" recently released by the National Cardiovascular Disease Center, there are about 290 million patients with cardiovascular and cerebrovascular diseases (including coronary heart disease, stroke, heart failure, hypertension, etc.) growth trend. The incidence of thrombotic diseases due to vascular embolism in cardiovascular and cerebrovascular diseases (such as cerebral thrombosis, cerebral infarction, myocardial infarction, heart failure, cardiogenic shock, coronary heart disease, atherosclerosis, etc. caused by thrombotic diseases) It is increasing year by year and showing a younger trend, and it has become a major public health problem in my country. Therefore, there is a great demand for drugs for the preve...

Claims

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Application Information

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IPC IPC(8): C07D213/30A61K31/4418A61P7/02A61P9/10A61P9/12A61P9/04A61P9/00A61P13/12
CPCA61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P13/12C07D213/30
Inventor 董旭娄红祥郑家晴于康任传杰张涛杨学谦
Owner SHANDONG UNIV
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