CN114010635A

CN114010635A - New application of nilapanib and derivatives thereof

Info

Publication number: CN114010635A
Application number: CN202111381376.8A
Authority: CN
Inventors: 王成
Original assignee: Tongji Medical College of Huazhong University of Science and Technology
Current assignee: Tongji Medical College of Huazhong University of Science and Technology
Priority date: 2021-11-21
Filing date: 2021-11-21
Publication date: 2022-02-08

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a novel application of nilapanib and a derivative thereof. Application of nilapanib or a derivative thereof in preparation of a preparation for inhibiting PDGFR beta expression and/or PDGFR beta downstream signaling pathway. Application of nilapanib or a derivative thereof in preparing a preparation for inhibiting smooth muscle phenotype switching. Application of nilapanib in preparing medicine for preventing and treating vascular diseases. The concentration of the nilapanib in the medicine for preventing and treating vascular diseases is 0.5 mu M or 20 mg/kg/d. An agent for inhibiting PDGFR β expression and/or PDGFR β downstream signaling pathway, comprising nilapanib or a derivative thereof as an active ingredient. Application of nilapanib or a derivative thereof in preparing a preparation for promoting alpha SMA gene expression. The nilapanib provided by the invention can be used as a PAPR1/2 inhibitor and has an inhibitory effect on PDGFR beta, so that the nilapanib can inhibit smooth muscle phenotype transition, and can prevent and/or treat restenosis after vascular injury.

Description

New application of nilapanib and derivatives thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel application of nilapanib and a derivative thereof.

Background

Nilapanib, also known as zejua, MK-4827, Niraparib, jele, nilapali; CAS: 1038915-60-4; the chemical name is dis 2- {4- [ (3S) -piperidine-3-yl ] phenyl } -2Hindazole 7-carboxamide 4-methyllbenzenesulfonate hydrate (1:1: 1). Is an organic matter with a chemical formula of C26H30N4O5S, white to off-white, and does not absorb water. The molecular weight was 510.61 amu. The structural formula is shown in fig. 9.

Nilaparib has been studied mainly as a PARP inhibitor, i.e., a selective PARP1/2 inhibitor, in the current state. The Niraparib is combined with nicotinamide adenine dinucleotide + (nicotinamide adenine dinucleotide +, NAD +) of PARP1 and/or PARP2 in a highly selective manner, so that the separation of PARP and DNA is prevented, cancer cells cannot be subjected to subsequent DNA repair, a large amount of genome damage (genomic damage) is accumulated in the tumor cells, the tumor cells are self-destroyed (self-destruct), and finally the purpose of treating tumors is achieved. In vitro studies show that niraparib-induced cytotoxicity may be involved in the inhibition of PARP enzyme activity and in the increased formation of PARP-DNA complexes leading to DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in BRCA1/2 tumor cell lines with or without defects. Xenograft models of mouse tumor cells deficient in BRCA1/2 and Niraparib, a model of derived transplantable tumors in patients with homologous recombination or mutations or wild-type BRCA1/2 deficiency in humans, reduced tumor growth. Therefore, the above drugs are widely used in recurrent epidermal ovarian, fallopian tube, or primary peritoneal cancer patients as a maintenance therapy for platinum-based chemotherapy in patients with complete or partial remission in adult patients.

In recent years, the incidence of coronary heart disease in China is on the rise. Coronary heart disease is a vascular disease with vascular stenosis caused by atherosclerosis as the main pathological process. Interventional therapy and coronary artery bypass grafting effectively improve many clinical symptoms of complex and critical coronary heart disease, however, restenosis at the site of vascular disease remains one of the major clinical problems that plague today. In the pathological process of restenosis after atherosclerosis and angioplasty, endothelial cells are damaged under the action of factors such as pressure and inflammation, so that abnormal proliferation of vascular smooth muscle cells is caused, and the vascular smooth muscle cells are transformed from contractile smooth muscle cells to secretory smooth muscle cells, thereby thickening the vascular wall and narrowing the lumen. Under pathological conditions such as hypertension, vascular smooth muscle is subjected to different shearing forces to generate phenotypic transformation, so that vascular remodeling is caused.

Vascular smooth muscle cell phenotypic transformation is an important pathophysiological process mediating membranous calcification in blood vessels. In normal vascular tissue, Vascular Smooth Muscle Cells (VSMCs) exhibit a contractile phenotype, are highly differentiated cells, and have the primary functions of maintaining the morphology of blood vessels and regulating vasoconstriction and tone, with characteristics of low proliferation, low migration, and low secretion. Major marker proteins such as smooth muscle alpha actin (SM α actin), smooth muscle 22 α, smooth muscle myosin heavy chain, etc. Various cardiovascular risk factors become inducers for driving Vascular Smooth Muscle Cell (VSMC) phenotype transdifferentiation, and can induce smooth muscle cell transdifferentiation from a contractile type (differentiation type) to a synthetic type (dedifferentiation type), and the cells have the characteristics of high proliferation, high migration and high protein secretion. Research shows that VSMCs phenotype transformation is a key step for the occurrence and development of a plurality of vascular diseases such as atherosclerosis, hypertension, restenosis after angioplasty and the like.

The vascular restenosis is a complex pathological process, effectively solves the clinical problems of the vascular restenosis, and can greatly expand the application of angioplasty, thereby better applying the blood flow re-transport operation to patients with vascular proliferative diseases and the like and maintaining the health of human beings. At present, there are several drugs used in scientific research to inhibit restenosis after vascular injury, among which the most common are: anti-inflammatory drugs (such as dexamethasone and estrogen), anti-cell proliferation agents (such as rapamycin, sirolimus and paclitaxel), Angiotensin Converting Enzyme (ACE) inhibitors cilazapril and spirapril, and coating drugs [ such as antithrombotic agents (such as hirudin and heparin) used in drug-coated stents (DES) ]. Previous studies have shown that Niraparib can exert therapeutic effects in tumor diseases by promoting apoptosis, and its role in restenosis after vascular injury has not been studied.

Disclosure of Invention

Aiming at the problems, the invention provides new application of the nilapanib and the derivatives thereof, mainly provides a new treatment scheme aiming at smooth muscle degeneration, develops new application of the nilapanib and expands application prospect of the nilapanib.

In order to solve the problems, the invention adopts the following technical scheme:

application of nilapanib or a derivative thereof in preparation of a preparation for inhibiting PDGFR beta expression and/or PDGFR beta downstream signaling pathway.

Application of nilapanib or a derivative thereof in preparing a preparation for inhibiting smooth muscle phenotype switching.

In some forms, the smooth muscle phenotype transitions to a contractile phenotype to a synthetic phenotype.

Application of nilapanib or a derivative thereof in preparing a medicament for preventing and treating vascular diseases.

In some forms, vascular disease includes tunica media calcification, atherosclerosis, hypertension, endothelial cell hyperproliferation due to vascular injury, and vascular restenosis.

In some embodiments, the restenosis includes restenosis following vascular injury.

In some embodiments, restenosis after vascular injury comprises PCI restenosis, in-stent restenosis, or restenosis after bypass grafting.

In some modes, the concentration of the nilapanib effect in the vascular disease prevention and treatment drug is 0.5-5 μ M or 5-20 mg/kg/d; preferably, the concentration used is 0.5. mu.M or 20 mg/kg/d.

An agent for inhibiting PDGFR β expression and/or PDGFR β downstream signaling pathway comprising nilapanib or a derivative thereof as an active ingredient.

Application of nilapanib or a derivative thereof in preparing a preparation for promoting alpha SMA gene expression.

The invention has the beneficial effects that:

nilaparib has an inhibitory effect on PDGFR beta, so that Niraparib can inhibit smooth muscle phenotype switching, thereby preventing and/or treating restenosis after vascular injury. Furthermore, nilapanib has no cytotoxic effect typical of cardiovascular drugs or other inhibitors of smooth muscle phenotype switch, and therefore its safety can be expected. It can be widely used as a medicine for treating related diseases involving smooth muscle, such as vascular restenosis, tumor and the like.

Drawings

In fig. 1, a is a group of a pseudo operation and a carrier treatment, b is a group of a ligation and a carrier treatment, c is a group of a ligation and a nilapani treatment, and the morphology of a blood vessel of a rat after carotid artery ligation is detected by an oil red-Hematoxylin (HE) staining experiment;

FIG. 2 shows VSMC proliferation assay using EdU assay with varying concentrations of Niraparib and vehicle (DMSO);

FIG. 3 shows stimulation of VSMC with Niraparib (0.5,1, 5. mu.M) and vehicle (DMSO) following PDGF-BB administration. In the figure, the expression of cyclin and oncostatin is detected by using a PCR (polymerase chain reaction) experiment after the Niraparib and the carrier with different concentrations, and the cyclin expression is increased and the oncostatin expression is reduced after the VSMC is treated by PDGF-BB; after the Niraparib is given for stimulation, the cyclin expression is reduced, and the cancer suppressor protein expression is increased;

FIG. 4 shows stimulation of VSMC with Niraparib (0.5,1, 5. mu.M) and vehicle (DMSO) following PDGF-BB administration. In the figure, the expression and the activity of Caspase 3 are detected by the Niraparib and the carrier with different concentrations, and no obvious change is seen;

FIG. 5 shows stimulation of VSMC with Niraparib (0.5,1, 5. mu.M) and vehicle (DMSO) following PDGF-BB administration. In the figure, Niraparib with different concentrations is used for detecting the migration condition of cells by using a transwell experiment;

FIG. 6 shows stimulation of VSMC with Niraparib (0.5,1, 5. mu.M) and vehicle (DMSO) following PDGF-BB administration. In the figure, Niraparib with different concentrations is used for detecting the proliferation and migration of cells by using a scratch experiment;

in FIG. 7, after the carotid artery of the rat is ligated, the rat is treated with a vector and 20mg/kg dNairaparib, and the Niraparib with different concentrations is used for detecting the expression of the contractile gene alpha SMA by an immunofluorescence experiment;

FIG. 8 shows stimulation of VSMC with Niraparib (0.5,1, 5. mu.M) and vehicle (DMSO) following PDGF-BB administration. In the figure, the expression level of PDGFR beta is detected by using western blot experiments for Niraparib with different concentrations;

FIG. 9 is a Nilaparib structural formula.

Detailed Description

The term is defined as:

the term "nilapani derivative"The nilapanib derivative is a compound which is different from nilapanib in partial position structure and functional group change, but the structure and functional group change of the positions keeps the nilapanib derivative and the nilapanib derivative still have the same similar control and regulation effects on the diseases related to the invention. For example, derivatives of nilapanib moiety-H or functional group-NH 2, altered, are intended to be within the scope of the present invention as long as they are capable of modulating the conditions to which the present invention relates. In some aspects described below, the nilapanib derivative is intended to be equivalent in scope to the nilapanib derivative in substantially the same effect as nilapanib for the treatment of the same condition, although the mechanisms involved are substantially the same and are intended to fall within the scope of the corresponding claims.

The term "control"Refers to the medical management of a patient with the intent to cure, ameliorate, stabilize or prevent a disease, pathological condition or disorder. The term includes active treatment, i.e., treatment specifically directed to the amelioration of a disease, pathological condition, or disorder, and also includes causal treatment, i.e., treatment directed to the removal of the cause of the associated disease, pathological condition, or disorder. In addition, the term also includes palliative treatments, i.e., treatments designed to alleviate symptoms rather than cure a disease, pathological condition, or disorder; prophylactic treatment, i.e. treatment aimed at minimising or partially or completely inhibiting the development of the relevant disease, pathological condition or disorder; and supportive treatment, i.e. treatment for supplementing another specific therapy directed to an improvement of the relevant disease, pathological condition or disorder. Meanwhile, in commercial activities, if a product containing the same components as the present invention is produced, the product specification does not describe the same similar use as the present invention, but it should be regarded as an application when it gives a hint that the corresponding product is used for achieving the same purpose as the present invention.

The definitions of the terms used herein are to be construed as being given their ordinary meaning in the art unless otherwise indicated. In the absence of counterexamples, no diminutive explanation is made, i.e., except for the case where evidence of counterexamples exists, the rest should fall within the scope.

The invention is further illustrated below:

a first aspect of this section relates to:

The purpose of inhibiting the expression of PDGFR β is mainly to keep it at a normal level and to prevent it from being abnormally changed to cause lesions. The purpose of inhibiting the expression of the PDGFR β downstream pathway is also to keep it at a normal level and prevent its abnormal changes from causing lesions. Wherein the normal level in this paragraph is medically indicated as a medical reference value, which is subject to a decrease in inhibition when the expression is ultrahigh. However, it is within the scope of the invention if it is used for some extreme purposes. For example, in some environments, when PDGFR β expression needs to be controlled to be greatly reduced and PDGFR β downstream pathway expression needs to be controlled to the maximum extent; for another example, PDGFR β expression is prevented from increasing to maintain a certain level, and PDGFR β downstream pathway expression is maintained at a certain level.

When the polypeptide is used in other ways, the polypeptide can also be directly added to a substance to be regulated, for example, in commercial research experiments, when the polypeptide is used as a PDGFR beta expression and/or PDGFR beta downstream pathway expression regulating reagent, the polypeptide can be directly added to relevant cell sap to achieve the same basic purpose of the invention, and the polypeptide and the cell sap are also within the scope of the invention.

The PDGFR beta downstream pathway expression inhibitor related to the invention is not limited to the specific application mode, and also belongs to the relevant content of the aspect when the inhibitor is used for preparing medicines for treating diseases related to, for example, PDGFR beta downstream pathway overexpression triggering.

In some embodiments, the agent that inhibits PDGFR β expression and/or PDGFR β downstream pathway expression is present at a concentration of 0.5 to 5 μ M or 5 to 20 mg/kg/d; preferably, the concentration used is 0.5. mu.M or 20 mg/kg/d. Wherein the action concentration is used for treatment, the specific concentration parameter (content index) refers to the concentration of effective components in the conventional medicine, and the effective component can be made into preparation or medicine granule, and the application method is oral administration or injection.

A second aspect of this section relates to:

Whether vascular smooth muscle cells can maintain the contractile phenotype is a key link in determining vascular homeostasis and remodeling. Inhibition of smooth muscle to other phenotypes can cause some pathologies.

In some embodiments, the smooth muscle phenotype switch comprises a switch from contractile to secretory. The transition from systolic to secretory is inhibited by nilapanib, particularly nilapanib.

A third aspect of this section relates to:

In some embodiments, vascular diseases including tunica media calcification, atherosclerosis, hypertension, endothelial cell hyperproliferation caused by vascular injury, and vascular restenosis, and cardiovascular disorders caused by other proximate pathogenic mechanisms are also within the scope of the present invention.

In some embodiments, restenosis following vascular injury includes PCI restenosis, in-stent restenosis, restenosis following bypass grafting, and other conditions with similar pathogenesis.

Can be used for preventing and treating restenosis after vascular injury. If aiming at some patients who have coronary stent operation and the like, the nilapanib can also play a role in subsequent adjuvant therapy, and further play a role in preventing restenosis of blood vessels; adjunctive therapeutic agents similar to these should also be within the scope of the invention.

A fourth aspect of this section relates toAnd:

an agent for inhibiting PDGFR β expression and/or PDGFR β downstream signaling pathway, comprising nilapanib as an active ingredient.

The nilapanib derivative is a compound that has a partial functional group and a carbon chain length that varies from that of nilapanib.

The inhibitor is a mixture containing Nilaparib and other drugs; wherein the effective action concentration of the nilapanib in the inhibitor on the corresponding mechanism is 0.5 mu M or 20 mg/kg/d.

Taking nilapanib or a derivative thereof as an example, the inhibitor comprises at least one of nilapanib or a derivative thereof:

one of the inhibitors contains the effective component of Nilaparib and other auxiliary drugs, thereby forming a novel pharmaceutical composition with inhibitory effect on PDGFR beta expression and/or PDGFR beta downstream pathway expression.

In the second aspect, the inhibitor contains an active ingredient nilapanib derivative and other auxiliary drugs, thereby forming a novel pharmaceutical composition having an inhibitory effect on PDGFR β expression and/or PDGFR β downstream pathway expression.

Therefore, the nilapanib or the derivative thereof is mixed with other components to form a novel preparation and a novel medicine for preventing and treating related diseases.

A fifth aspect of this section relates to:

application of nilapanib or a derivative thereof in preparing a preparation for promoting alpha SMA gene expression. The promoting effect is mainly determined according to the treatment purpose, and can be expressed as exceeding the normal level or maintaining the normal level.

The sixth aspect of this section is described in conjunction with specific items:

the Niraparib used in the tests of this example was purchased from seleck, catalog No.: s2741 alias: MK-4827. The phenotypic switching of VSMC in the following experiments was examined using the methods in the following steps, respectively.

Experiment one

After carotid artery ligation injury or sham-operated injury in C57BL/6 rats, Niraparib (20 mg/kg. d) and vehicle (DMSO) were intraperitoneally injected, respectively. After 14 days, the mice were euthanized and the injured blood vessels were subjected to a vascular resection procedure. After paraffin is fixed and embedded by formaldehyde with the mass concentration of 4%, the blood vessel is cut into sections. FIG. 1 shows the detection of the vascular morphology of a rat carotid artery after ligation by using an oil red-Hematoxylin (HE) staining experiment after treatment of a sham operation + carrier treatment group, a ligation + carrier treatment group and a ligation + Nilaparib treatment group. The results are shown in FIG. 1. Wherein, the figure 1 is a statistical chart of the average thickness of the carotid artery of a rat in a sham operation + carrier treatment group, a ligation + carrier treatment group and a ligation + nilapani treatment group from left to right. As can be seen from fig. 1, when rats were subjected to carotid artery ligation, the carotid artery was increased in thickness, i.e., vascular injury resulted in excessive proliferation of vascular endothelial cells, compared to the sham surgery + vehicle treatment group; and the nilapanib can inhibit the excessive proliferation of the endothelial cells in the blood vessels caused by the blood vessel injury.

Experiment two

VSMC cells were treated with PDGF-BB (30ng/ml) and stimulated with different concentrations of Niraparib (0.5. mu.M, 1. mu.M, 5. mu.M) and vehicle DMSO, respectively. FIG. 2 shows VSMC proliferation assay using EdU assay for varying concentrations of Niraparib. In FIG. 2, the first column is the DAPI stained nuclei, the second column is the EdU stained nuclei, and the third column is the fusion map of the first two columns; while the first row was a vector treated group, the second row was a PDGF-BB and vector treated group, the third row was a PDGF-BB and 0.5. mu.M Niraparib treated group, the fourth row was a PDGF-BB and 1. mu.M Niraparib treated group, and the fifth row was a PDGF-BB and 5. mu.M Niraparib treated group. As can be seen from fig. 2, after VSMC cells were treated with PDGF-BB, EdU-positive cells increased, and after further treatment with Niraparib, EdU-positive cells decreased, and the amount of EdU-positive cells decreased as the concentration of Niraparib increased. In conclusion, after the VSMC cells are treated by the PDGF-BB, the proliferation of the VSMC cells can be promoted, and the Niraparib can inhibit the PDGF-BB-induced cell proliferation, and the inhibition effect is enhanced along with the increase of the concentration of the Niraparib.

EdU cell proliferation assay: rat-derived primary cells (VSMC) were seeded in 96-well plates and treated with different concentrations (0.5. mu.M, 1. mu.M, 5. mu.M) of Niraparib and vehicle DMSO, respectively, for 4 h. After 48h, the four treatments were stimulated with PDGF-BB (30ng/ml) for 48h (control with an equal volume of DSMO), and EdU incorporation was analyzed according to the manufacturer's instructions and photographed with an Olympus cellSens Entry.

Experiment three

After VSMC cells were treated with PDGF-BB (30ng/ml), they were stimulated with different concentrations of Niraparib (0.5. mu.M, 1. mu.M, 5. mu.M) and DMSO, cells were collected, and after protein extraction, cyclin and oncostatin expression was detected by Polymerase Chain Reaction (PCR) assay, as shown in FIG. 3. VSMC cells expressed cyclin (PCNA, CyclinD1) and oncostatin (P27, P21) under different treatments. As shown in FIG. 3, after treatment with PDGF-BB, the expression of cyclin was increased and the expression of oncostatin was decreased in VSMC cells; after the Niraparib is given for stimulation, the cyclin expression is reduced, and the cancer suppressor protein expression is increased; the expression level of the protein related to the apoptosis has no obvious change.

Experiment four

After VSMC cells are treated by PDGF-BB (30ng/ml), Niraparib (0.5 mu M,1 mu M and 5 mu M) and carrier DMSO with different concentrations are respectively given for stimulation, the cells are collected, after protein is extracted, Caspase 3 expression and activity kit (BIOMOL) experiments are utilized to detect the apoptosis level, and the result is shown in figure 4. As can be seen from FIG. 4, the different concentrations of Niraparib had no significant effect on apoptosis.

Experiment five

VSMC cells were treated with PDGF-BB (30ng/ml) and stimulated with different concentrations of Niraparib (0.5. mu.M, 1. mu.M, 5. mu.M) and vehicle DMSO, respectively, to detect cell migration using the transwell assay. The results are shown in FIG. 5. As shown in FIG. 5, PDGF-BB promotes cell migration, while Niraparib inhibits cell migration, and the inhibition increases with increasing concentration.

Cell migration was measured by the Transwell method: VSMC was pretreated with Niraparib for 4h, seeded in the upper chamber, 500L DMEM and fetal bovine serum at 10% concentration by volume and PDGF-BB (30ng/ml) placed in the lower chamber. After 24h, the cells were fixed in the lower air chamber with 4% by mass of formaldehyde for 20 minutes and stained with 0.1% by mass of crystal violet for 20 minutes. Migrated cells were photographed using the Olympus cellSens channel.

Experiment six

VSMC were stimulated with different concentrations of Niraparib (0.5. mu.M, 1. mu.M, 5. mu.M) and vehicle DMSO after PDGF-BB treatment (30ng/ml) and examined for cell proliferation and migration by the scratch assay, as shown in FIG. 6. From FIG. 6, it is seen that PDGF-BB promotes the rate of closure of cell scratch, while Niraparib inhibits the promotion, and that the inhibition of cell scratch closure is increased with the increase of the concentration of Niraparib.

Cell scratch test: VSMC were seeded into 6-well plates and cultured to 80% density. The cell monolayer was scratched with a 1ml pipette tip. After pre-incubation of cells with different concentrations of Niraparib for 4h, the cells were stimulated with PDGF-BB (30ng/ml) for 48h (control group with equal volume of DSMO) and then cultured in DMEM containing 10% by volume fetal bovine serum. Cells were visualized using an Olympus cellSens entry and wound closure rate was measured using the Image J program.

Experiment seven

After the carotid artery of a rat is respectively ligated, the rat is treated by a carrier DMSO and 20mg/kg dNairanib, the expression condition of the contractile gene alpha SMA is detected by an immunofluorescence experiment, a tissue section is incubated overnight at 4 ℃ by using an SM alpha-actin primary antibody (the volume ratio is 1: 100), and then incubated for 2 hours at 37 ℃ by using a FITC-conjugated fluorescent secondary antibody. Nucleic acids were stained with DAPI at 37 ℃ for 15 min. The sections were finally visualized using an Olympus cellSens entry. Carotid morphology was observed and the results are shown in FIG. 7. In fig. 7, the first column is the sham-operated and empty-load treatment group, the second column is the operated and empty-load treatment group, the third column is the operated and Niraparib treatment group, and the first row is the immunofluorescence staining of carotid artery α SMA, the second row is the staining of carotid artery nuclei by DAPI, and the third row is the fusion map of the first two rows. As shown in FIG. 7, after the rat was ligated to the carotid artery, the carotid artery wall was thickened, and the expression level of the contractile gene α SMA in the carotid artery was decreased; after further treatment with Niraparib, the carotid wall thickness decreased and the expression level of the contractile gene alpha SMA increased. After the blood vessel is damaged, the blood vessel wall is thickened, and the expression quantity of the contraction gene alpha SMA is reduced.

Experiment eight

After the VSMC cells were treated with PDGF-BB, they were stimulated with different concentrations of Niraparib (0.5. mu.M, 1. mu.M, 5. mu.M) and vehicle DMSO, respectively, and the level of PDGFR β protein was detected by Western blotting, as shown in FIG. 8. From fig. 8, it can be seen that PDGFR β protein levels decreased with increasing concentrations of Niraparib after VSMC cells were treated with PDGF-BB and further treated with Niraparib. Therefore, Niraparib inhibited protein expression of PDGFR β, and this inhibition was increased with increasing Niraparib concentration.

From the experimental results, it is clear that nilapanib can directly inhibit the phenotypic transformation of VSMC.

It will be apparent to those skilled in the art that various modifications may be made to the above embodiments without departing from the general spirit and concept of the invention. All falling within the scope of the present invention. The protection scheme of the invention is subject to the appended claims.

Claims

1. Application of nilapanib or a derivative thereof in preparation of a preparation for inhibiting PDGFR beta expression and/or PDGFR beta downstream signaling pathway.

2. Application of nilapanib or a derivative thereof in preparing a preparation for inhibiting smooth muscle phenotype switching.

3. Use according to claim 2, wherein the smooth muscle phenotype is switched to a contractile to a synthetic phenotype.

4. Application of nilapanib or a derivative thereof in preparing a medicament for preventing and treating vascular diseases.

5. The use of claim 4, wherein the vascular disease comprises tunica media calcification, atherosclerosis, hypertension, endothelial cell hyperproliferation due to vascular injury, and vascular restenosis.

6. The use of claim 5, wherein the restenosis comprises restenosis following vascular injury.

7. The use of claim 6, wherein the post-vascular injury restenosis comprises PCI restenosis, in-stent restenosis, post-bypass graft restenosis.

8. The use of claim 4, wherein the concentration of nilapanib present in the prophylactic or therapeutic agent is 0.5-5 μ M or 5-20 mg/kg/d; preferably, the concentration used is 0.5. mu.M or 20 mg/kg/d.

9. An agent for inhibiting PDGFR β expression and/or PDGFR β downstream signaling pathway, which comprises nilapanib or a derivative thereof as an active ingredient.

10. Application of nilapanib or a derivative thereof in preparing a preparation for promoting alpha SMA gene expression.