Application of compound in preparation of medicine for treating vascular remodeling

Abstract

The invention relates to the technical field of novel application of compounds, in particular to application of a compound in preparation of a medicine for treating vascular remodeling. According to the application of the compound shown in the formula I in preparation of the medicine for treating vascular remodeling, the compound # imgabs0 has a treatment effect on vascular remodeling diseases caused by abnormal proliferation of vascular smooth muscles, and the indication range of AAA-237 is expanded.

Description

Technical Field

[0001] The present invention relates to the technical field of new application of compounds, and in particular to the application of compounds in preparing drugs for treating vascular remodeling. Background Art

[0002] The structural formula of AAA-237 is as follows:

[0003] It is a Skp2 inhibitor that can inhibit the function of metastatic melanoma cells, slow down the cell cycle, inhibit cell proliferation, and induce apoptosis, thereby having a good therapeutic effect on cancer.

[0004] However, the prior art does not disclose the application of AAA-237 in cardiovascular diseases, especially in vascular remodeling.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] The purpose of the present invention is to provide a use of a compound in the preparation of a drug for treating vascular remodeling. The embodiments of the present invention provide a new use of a compound, which has a therapeutic effect on vascular remodeling diseases caused by abnormal proliferation of vascular smooth muscle, expanding the indication range of AAA-237.

[0007] The present invention is achieved in that:

[0008] In a first aspect, the present invention provides a use of a compound of formula I in preparing a drug for treating vascular remodeling.

[0009] In alternative embodiments, the vascular remodeling comprises atherosclerosis, in-stent restenosis, coronary artery bypass graft occlusion, or hypertension.

[0010] In an alternative embodiment, the drug is a drug that inhibits smooth muscle cell proliferation and migration.

[0011] In an optional embodiment, the drug is a drug that inhibits PDGF-BB-induced VSMCs phenotypic transformation, proliferation and migration.

[0012] In a second aspect, the present invention provides a use of a compound represented by formula I in the preparation of an inhibitor for inhibiting vascular intimal hyperplasia.

[0013] In an alternative embodiment, the inhibitor is an inhibitor of smooth muscle cell proliferation and migration;

[0014] Or it is an inhibitor of VMSCs proliferation, migration and phenotypic transformation induced by PDGF-BB.

[0015] In a third aspect, the present invention provides a use of a compound of formula I in the preparation of a medicament for treating complications after percutaneous coronary intervention.

[0016] In an alternative embodiment, the complication includes vascular restenosis or stent thrombosis.

[0017] In a fourth aspect, the present invention provides a use of a compound of formula I in the preparation of a medicament for treating complications after coronary artery bypass grafting.

[0018] In a fifth aspect, the present invention provides a use of a compound represented by formula I in the preparation of a drug for intervening in restenosis.

[0019] The present invention has the following beneficial effects: the compound AAA-237 provided in the embodiment of the present invention is confirmed by the PDGF-stimulated vascular smooth muscle cell proliferation and migration experiment that AAA-237 inhibits pathological vascular intimal hyperplasia, indicating that AAA-237 can be used as a new drug for the treatment of vascular remodeling diseases, can reduce the incidence of vascular restenosis after coronary artery bypass grafting and percutaneous coronary intervention, and can become a potential drug for intervening in restenosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0021] Figure 1 This is a result diagram of Experimental Example 1 of the present invention;

[0022] Figure 2 This is a result diagram of Experimental Example 2 of the present invention;

[0023] Figure 3 This is a result diagram of Experimental Example 3 of the present invention;

[0024] Figure 4 This is a result diagram of Experimental Example 2 of the present invention. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0026] Vascular remodeling refers to abnormal changes in the structure and function of the vascular wall caused by damage to the vascular wall due to diseases, mechanical stress, etc., which is usually manifested as thickening of the vascular wall and stenosis of the lumen. The mechanisms of vascular remodeling include proliferation and differentiation of VSMCs, degradation and rupture of elastin fibers, collagen deposition, and arterial calcification. Among them, phenotypic transformation of VSMCs plays a key role in regulating vascular development and remodeling. VSMCs present a "contractile phenotype" in normal blood vessels. They are highly differentiated and have a low proliferation rate, mobility, and the ability to secrete proteins. Under specific stimulation, they present a dedifferentiated state, with increased proliferation rate and mobility and secretion of a large amount of extracellular matrix. The corresponding "contractile phenotype" markers α-actin and smooth muscle protein 22α are expressed less, while the "secretionary phenotype" osteopontin is expressed more. This phenotypic transformation is regulated by multiple factors, including the intracellular and extracellular environment, cytokines, non-coding RNA, and drugs, among which platelet-derived growth factor (PDGF-BB) is one of its important regulatory factors. When the vascular endothelium is damaged, platelets, endothelial cells and inflammatory cells release PDGF-BB at the site of vascular injury and bind to PDGF receptors to activate downstream signaling pathways to promote VSMCs proliferation, migration, phenotypic transformation and synthesis of extracellular matrix, leading to vascular remodeling diseases. Therefore, inhibiting PDGF-BB-induced VSMCs phenotypic transformation is an important means to treat vascular remodeling diseases.

[0027] The present invention discovered that AAA-237 is a compound represented by the following formula I It can inhibit the proliferation and migration of vascular smooth muscle cells, and then has the effect of inhibiting angiogenesis intimal hyperplasia. Specifically, it can inhibit the proliferation, migration and phenotypic transformation of VSMCs induced by PDGF-BB, indicating that it can inhibit angiogenesis intimal hyperplasia, indicating that AAA-237 can be used as a new drug for the treatment of vascular remodeling diseases, can reduce vascular complications after coronary artery bypass grafting and percutaneous coronary intervention, such as the prevention and treatment of restenosis or stent thrombosis, and can become a potential drug for intervention in restenosis.

[0028] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0029] Experimental Example 1

[0030] Determination of the concentration of PDGF-BB to induce proliferation of A7r5 cells

[0031] method:

[0032] A7r5 cells (rat thoracic aorta smooth muscle cells) were seeded into 96-well plates at 5000 cells per well. After culturing for 24 hours, serum-free DMEM medium was replaced and cultured for another 24 hours to synchronize the cells. The synchronized cells were randomly divided into a control group and five PDGF-BB dose groups (5ng / mL, 10ng / mL, 20ng / mL, 40ng / mL, 80ng / mL). The control group was given serum-free medium for 24 hours, and the five PDGF-BB dose groups were cultured for 24 hours with serum-free medium containing 5ng / mL, 10ng / mL, 20ng / mL, 40ng / mL, and 80ng / mL PDGF-BB, respectively.

[0033] Results Participation Figure 1 ,according to Figure 1 It can be seen that 20 ng / mL of PDGF-BB can significantly promote the proliferation of A7r5 cells. Therefore, 20 ng / mL of PDGF-BB was selected to establish the abnormal proliferation model of A7r5 cells.

[0034] Experimental Example 2

[0035] Effect of AAA-237 on PDGF-BB-induced VSMCs proliferation

[0036] method:

[0037] The synchronized A7r5 cells were randomly divided into control group, PDGF-BB group and drug group. The control group was cultured with serum-free DMEM medium containing an equal volume of DMSO for 24 hours, the PDGF-BB group was cultured with serum-free DMEM medium containing 20ng / mL PDGF-BB for 24 hours, and the drug group was treated with serum-free DMEM medium containing 20ng / mL PDGF-BB and different concentrations of AAA-237 for 24 hours. Subsequently, 10μL CCK=8 solution was added to each well, and after incubation in a cell culture incubator for 1 hour, the absorbance value at 450nm was measured.

[0038] After the measurement, the survival rate was calculated based on the absorbance value.

[0039] Survival rate % = treatment group / control group * 100%; see the results Figure 2 ,according to Figure 2 It can be seen that AAA-237 has a concentration-dependent inhibitory effect on the abnormal proliferation of A7r5 cells induced by PDGF-BB.

[0040] Experimental Example 3

[0041] Effect of AAA-237 on PDGF-BB-induced VSMCs migration

[0042] method:

[0043] Take logarithmic phase A7r5 cells and evenly inoculate them into 24-well plates. When the cell confluence reaches about 90%, replace it with serum-free DMEM medium and culture it for 24 hours to homogenize the cells. Then set up a control group, a model group, and a low, medium, and high drug administration group. Each group was scratched with cells (a 200 μL gun tip drew a "cross" in the middle of the hole), then washed with PBS once and photographed, and the cell scratches at 0 hours were recorded. After the photo was taken, the control group added DMSO with a volume ratio of one thousandth, the model group added PDGF-BB (20ng / mL), and the drug administration group added PDGF-BB and low, medium, and high concentrations of AAA-237 at the same time. Take pictures at 24 hours to record the changes in the scratches.

[0044] Results Figure 3 ,according to Figure 3 It can be seen that AAA-237 has a concentration-dependent inhibitory effect on the abnormal migration of A7r5 cells induced by PDGF-BB.

[0045] Experimental Example 4

[0046] Effect of AAA-237 on intimal hyperplasia induced by ligation of left common carotid artery in mice

[0047] method:

[0048] C57 / BL6 male mice, 6-8 weeks old. Randomly divided into sham operation group, model group, low (5mg / kg), medium (10mg / kg), and high dose groups (20mg / kg), 10 mice in each group. Modeling method: intraperitoneal anesthesia with 0.75% sodium pentobarbital (0.1mL / 10g), fixed on the dissecting table, and the neck was depilated. The skin was cut along the middle of the neck, and the neck tissue was bluntly separated layer by layer to fully expose the left common carotid artery. The artery and the accompanying nerve were carefully separated, and the bifurcation of the external carotid artery and the internal carotid artery was ligated with No. 6 sterile braided sutures. Then, the incision was sutured and disinfected, and placed on a warming pad. After waking up, it was continued to be fed and observed. The sham operation group only laid the line without ligation. On the second day after the modeling, the drug component was intraperitoneally injected with different concentrations of AAA-237, and the sham operation group and the model group were injected with the corresponding solvent, and the drug was administered continuously for 14 days. After the administration, the mice were anesthetized and fixed, the mouse sternum was quickly cut open, the chest cavity was opened, the heart was exposed, the LongerPump peristaltic pump was turned on, the perfusion needle of the peristaltic pump was inserted into the apex of the heart and fixed, and a small hole was quickly cut in the right auricle (to facilitate blood outflow), and the blood in the mouse blood vessels was drained with normal saline through cardiac perfusion, and then the left neck ligature of the mouse was fully exposed, the left neck blood vessel was taken out with the ligature knot, and quickly immersed in 4% paraformaldehyde solution for fixation, and then the pathological morphological changes were observed by HE staining.

[0049] Results Figure 4 ,according to Figure 4 It can be seen that after surgery, the model group showed obvious intimal hyperplasia, but the intimal hyperplasia of the drug group was inhibited, indicating that AAA-237 has the effect of inhibiting angiogenesis intimal hyperplasia. Combined with the in vitro experimental data, it can be seen that this effect is mainly achieved by inhibiting the proliferation and migration of vascular smooth muscle cells.

[0050] It is further explained that AAA-237 provided in the embodiments of the present invention can be used to prepare drugs for inhibiting vascular neointimal hyperplasia, and is expected to be applied to the prevention and treatment of complications after percutaneous coronary intervention, such as restenosis or stent thrombosis, and can become a potential drug for intervening in restenosis.

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of a compound of formula I in the preparation of a drug for treating vascular remodeling, 2. The use according to claim 1, characterized in that: The vascular remodeling includes atherosclerosis, in-stent restenosis, coronary artery bypass graft occlusion or hypertension.

3. The use according to claim 1, characterized in that: The drug is a drug for inhibiting the proliferation and migration of smooth muscle cells.

4. The use according to claim 1, characterized in that: The drug is a drug for inhibiting PDGF-BB-induced VSMCs phenotype transformation, proliferation and migration.

5. Use of a compound of formula I in the preparation of an inhibitor for inhibiting vascular intimal hyperplasia, 6. The use according to claim 5, characterized in that: The inhibitor is an inhibitor that inhibits smooth muscle cell proliferation and migration; Or it is an inhibitor of VMSCs proliferation, migration and phenotypic transformation induced by PDGF-BB.

7. Use of a compound of formula I in the preparation of a drug for treating complications after percutaneous coronary intervention, 8. The use according to claim 7, characterized in that: The complications include vascular restenosis or stent thrombosis.

9. Use of a compound of formula I in the preparation of a drug for treating complications after coronary artery bypass grafting.

10. Use of a compound of formula I in the preparation of a drug for intervening in restenosis,

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