CN113332289A - Application of Pazopanib HCl compound in preparation of anti-EV 71 virus drugs - Google Patents
Application of Pazopanib HCl compound in preparation of anti-EV 71 virus drugs Download PDFInfo
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- CN113332289A CN113332289A CN202110509397.7A CN202110509397A CN113332289A CN 113332289 A CN113332289 A CN 113332289A CN 202110509397 A CN202110509397 A CN 202110509397A CN 113332289 A CN113332289 A CN 113332289A
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- 241000700605 Viruses Species 0.000 title claims abstract description 21
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title claims abstract description 14
- 241001529459 Enterovirus A71 Species 0.000 claims abstract description 33
- 230000000694 effects Effects 0.000 claims abstract description 19
- 230000005764 inhibitory process Effects 0.000 claims description 9
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- 239000007924 injection Substances 0.000 claims description 3
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- MQHIQUBXFFAOMK-UHFFFAOYSA-N pazopanib hydrochloride Chemical compound Cl.C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 MQHIQUBXFFAOMK-UHFFFAOYSA-N 0.000 abstract description 22
- 150000001875 compounds Chemical class 0.000 abstract description 15
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- 238000012360 testing method Methods 0.000 description 7
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- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 4
- 229960000639 pazopanib Drugs 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000020061 Hand, Foot and Mouth Disease Diseases 0.000 description 3
- 208000025713 Hand-foot-and-mouth disease Diseases 0.000 description 3
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- 208000006740 Aseptic Meningitis Diseases 0.000 description 1
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
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- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
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- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a Pazopanib HCl compound in preparation of an anti-EV 71 virus medicine. Through the research experiment of the activity of Pazopanib HCl against EV71, the compound Pazopanib HCl inhibits the cytopathic effect (CPE) generated by EV71 on a host cell RD, enhances the cell survival rate, reduces the yield of progeny viruses, and can be applied to the preparation of anti-EV 71 virus medicines.
Description
Technical Field
The invention relates to the technical field of antiviral drugs, and in particular relates to an application of a Pazopanib HCl compound in preparation of an anti-EV 71 virus drug.
Background
Enterovirus type 71 (EV71), a member of the Enterovirus genus (Enterovirus) of the Picornaviridae family (Picornaviridae), is one of the most prominent pathogens causing hand-foot-and-mouth disease in infants and young children, sometimes with severe central nervous system complications including aseptic meningitis, encephalitis, polio-like paralysis, neurological heart-lung failure, etc., and even death. The government of China has listed the hand-foot-and-mouth disease as a class C infectious disease in 2008 and brings into management, and a series of relevant laws and regulations are formulated to strictly control the epidemic spread of the hand-foot-and-mouth disease. There is currently no specific drug for the treatment of diseases infected by EV71, and related vaccines are marketed in 2015, and their preventive effects are yet to be further investigated. Therefore, the development of specific and effective anti-EV 71 medicaments is imperative.
Pazopanib HCl, a novel multi-target inhibitor, acts on VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-fms, with IC50 being 10nM, 30nM, 47nM, 84nM, 74nM, 140nM and 146nM, respectively, in cell-free assays. Pazopanib is currently the first and only one tyrosine kinase inhibitor approved for the treatment of multiple histological subtypes of Soft Tissue Sarcoma (STS). Originally developed as small molecule inhibitors of vascular endothelial growth factor receptors, preclinical studies have shown that Pazopanib exerts an anti-cancer effect by inhibiting angiogenesis and oncogenic signaling pathways. Pazopanib was studied in STS after the optimal dose and safety were determined in early studies and approved for treatment of advanced renal cell carcinoma. Pazopanib has been rarely reported for antiviral therapy.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to evaluate the inhibition activity of Pazopanib HCl on EV71 virus, and aims to provide the application of Pazopanib HCl compound in preparing anti-EV 71 virus medicaments, namely the Pazopanib HCl is used as an anti-EV 71 virus screening compound.
In order to achieve the purpose, the invention provides an application of a Pazopanib HCl compound in preparing an anti-EV 71 virus medicine, which is characterized in that: the Pazopanib HCl compound with anti-EV 71 activity, namely C21H23N7O2S & HCl, chemical structural formula as follows:
preferably, the inhibition rate of the Pazopanib HCl compound on EV71 at 50 μ M is 84.7%.
Furthermore, the medicine refers to a Pazopanib HCl compound which is prepared into a preparation for resisting EV71 virus by adding pharmaceutically acceptable auxiliary materials and carriers.
Further, the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
The invention has the following advantages and beneficial effects:
the object of the invention is achieved in that Pazopanib HCl is tested for activity by standard virus activity test methods. According to the invention, through a large number of biological experiments, Pazopanib HCl is found to have the activity against EV71 virus. The recombinant adenovirus can inhibit cytopathic effect caused by EV71 virus, enhance the survival rate of infected cells, inhibit the replication and proliferation of EV71 virus in cells, and reduce the yield of progeny virus. Therefore, the compound has potential to prepare specific therapeutic drugs for resisting EV71 infection and has a great clinical application prospect.
Drawings
Figure 1 is a graph of the effect of the multi-kinase inhibitor Pazopanib HCl on RD cell viability with EV71 action.
Figure 2 is the inhibitory effect of the multi-kinase inhibitor Pazopanib HCl on EV 71-induced RD cell CPE.
FIG. 3 is a graph of inhibition of the progeny virus production of EV71 by the multi-kinase inhibitor Pazopanib HCl.
FIG. 4 is the chemical structure of the multi-kinase inhibitor Pazopanib HCl.
Detailed Description
The multi-kinase inhibitor Pazopanib HCl used in the present invention was purchased from reagent companies. The invention relates to application of a multi-kinase inhibitor Pazopanib HCl in preparation of an anti-EV 71 virus drug, which is to add pharmaceutically acceptable auxiliary materials and carriers to the multi-kinase inhibitor Pazopanib HCl to prepare an anti-EV 71 virus preparation. The preparation is granule, tablet, pill, capsule, injection or dispersant.
The multi-kinase inhibitor Pazopanib HCl of the invention has the following chemical structural formula:
the application of the multi-kinase inhibitor Pazopanib HCl as an anti-EV 71 virus shows that the multi-kinase inhibitor Pazopanib HCl has an obvious anti-EV 71 virus effect. Therefore, the compound has potential to prepare specific therapeutic drugs for resisting EV71 infection and has a great clinical application prospect.
Example 1
The invention carries out anti-EV 71 activity research experiments on the compounds, and the experimental conditions are as follows: hereinafter, materials and operation methods used in the present invention are well known in the art, if not specifically described.
1. The test contents are as follows:
analysis of compound anti-EV 71 activity: the invention combines a cytopathic effect analysis method and a cell survival rate detection method of MTT (methyl thiazolyl tetrazolium) determination to evaluate the activity of a multi-kinase inhibitor Pazopanib HCl against EV 71.
2. The test method comprises the following steps:
2.1.1 toxicity of Compounds on host RD cells
RD cells were plated in 96-well plates at 37 ℃ with 5% CO2After the culture box is cultured to grow a monolayer, cell culture solution is discarded, cell maintenance solutions containing test compounds with different concentrations are respectively added for continuous culture, the cytotoxicity is visually observed and respectively recorded by a microscope after 48 hours, and the cell survival rate is measured by an MTT method. The SPSS 11.5 software calculates the Median cytotoxic concentration of the drug for the cells (CC 50). Cell survival rate ═ (mean OD of drug groups)492Value/cell control mean OD492Value) × 100%.
2.1.2 inhibitory Activity of Compounds on EV71
RD cells were plated in 96-well plates at 37 ℃ with 5% CO2After the incubator is used for culturing full monolayer, the culture solution is discarded, cells are infected by EV71 virus solution of 100TCID50 for 1.5h, and test compounds (ribavirin serving as a positive control drug) with different concentrations are added for cell incubation. After the culture is continued for about 48 hours, the cytopathic effect (CPE) is observed under a microscope when about 90% of CPE lesions appear in the virus control wells. Observation and recording method of CPE: no cytopathic effects are noted-less than 25% cytopathic effects are noted +, 25-50% of cytopathic effects are designated as ++, 50% -75% are designated as +++, and more than 75% are designated as ++++.
After CPE observation is finished, the inhibition rate of the drug on EV71 is detected by using an MTT method. The method comprises the following specific steps: MTT 50. mu.L (5 mg. multidot.mL) was added to each well-1) After incubation for 3-4h, the supernatant was removed and an equal volume of DMSO was added to dissolve the pellet. The absorbance (OD) at 492nm was read with a microplate reader492Value). The inhibition rate of the drug on EV71 was calculated using the following formula. The half effective Concentration of the drug (Concentration for 50% of maximum effect, EC50) was calculated using SPSS 11.5 software.
2.1.3 Therapeutic Index (TI) of drug
TI CC50/EC 50. A higher therapeutic index indicates greater antiviral potential.
3. Results of the experiment
TABLE 1 Multi-kinase inhibitor Pazopanib HCl cytotoxicity and anti-EV 71 Activity
The results of the compound cytotoxicity and anti-EV 71 activity tests are shown in table 1. The effect of concentration-dependent compounds on RD cell viability with EV71 action is shown in figure 1. The maximum inhibition of Pazopanib HCl at 50. mu.M was found to be about 84.7%.
Example 2
The invention carries out intensive research on the activity of a multi-kinase inhibitor Pazopanib HCl against EV71, and carries out an inhibition effect test of the compound on the yield of EV71 progeny viruses, wherein the test conditions are as follows:
1. content of the experiment
Compounds were tested for inhibition of EV71 progeny virus production following EV71 infection of RD cells.
2. Test method
Logarithmic generatorLong term RD cells plated in 24 well plates 100TCID after confluency of monolayers50EV71 infected cells were incubated at 37 ℃ for 1.5h, virus solution removed, washed three times with PBS, and cell maintenance solution containing 50. mu.M concentration was added. Collecting cells and supernatant culture solution after 48h, freeze thawing and cracking at-20 deg.C and 37 deg.C for three times, and performing TCID50Methods EV71 virus titers were determined.
3. Test results
As shown in FIG. 3, the compound-treated RD cells all showed a significant reduction in viral titer relative to the viral control, with a 4.7log reduction relative to the viral control.
In conclusion, the multi-kinase inhibitor Pazopanib HCl has strong activity of inhibiting EV71, can inhibit RD cytopathic effect caused by EV71 virus, and can be prepared into a medicament for clinically and effectively resisting EV71 infection.
Claims (4)
1. The application of Pazopanib HCl compound in preparing anti-EV 71 virus medicines is characterized in that: the Pazopanib HCl compound with anti-EV 71 activity, namely C21H23N7O2S & HCl, chemical structural formula as follows:
2. the use of Pazopanib HCl compound according to claim 1, in the preparation of a medicament against EV71 virus, characterized in that: the inhibition of EV71 by the Pazopanib HCl compound at 50 μ M was 84.7%.
3. Use of the Pazopanib HCl compound according to claim 1 or 2, in the preparation of a medicament against EV71 virus, characterized in that: the medicine is prepared by adding pharmaceutically acceptable auxiliary materials and carriers into a Pazopanib HCl compound to prepare a preparation for resisting EV71 virus.
4. The use of Pazopanib HCl compound according to claim 3, in the preparation of a medicament against EV71 virus, characterized in that: the preparation is any one of granules, tablets, pills, capsules, injections or dispersing agents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115105507A (en) * | 2022-05-21 | 2022-09-27 | 复旦大学 | Application of pazopanib in preparation of medicine for inhibiting enterovirus 71 type neurotropic viral |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822120A (en) * | 2016-12-21 | 2017-06-13 | 湖北工业大学 | Application of two kinds of nitrogen heterocyclic ring esters compounds in anti-enterovirns type 71 medicine is prepared |
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- 2021-05-11 CN CN202110509397.7A patent/CN113332289A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106822120A (en) * | 2016-12-21 | 2017-06-13 | 湖北工业大学 | Application of two kinds of nitrogen heterocyclic ring esters compounds in anti-enterovirns type 71 medicine is prepared |
Non-Patent Citations (1)
| Title |
|---|
| JANE L. ROBERTS ET AL.: ""GRP78/Dna K Is a Target for Nexavar/Stivarga/Votrient in the Treatment of Human Malignancies, Viral Infections and Bacterial Diseases"" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115105507A (en) * | 2022-05-21 | 2022-09-27 | 复旦大学 | Application of pazopanib in preparation of medicine for inhibiting enterovirus 71 type neurotropic viral |
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