CN109602749A - Drug and its pharmaceutical applications of the Bu Linibu as treatment dengue virus infection - Google Patents
Drug and its pharmaceutical applications of the Bu Linibu as treatment dengue virus infection Download PDFInfo
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- CN109602749A CN109602749A CN201910110917.XA CN201910110917A CN109602749A CN 109602749 A CN109602749 A CN 109602749A CN 201910110917 A CN201910110917 A CN 201910110917A CN 109602749 A CN109602749 A CN 109602749A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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Abstract
The present invention relates to the drugs and its pharmaceutical applications for the treatment of dengue virus infection, specifically, disclose the purposes of compound shown in Formulas I or its drug acceptable salt in the drug for treating or preventing flavivirus virus infection
Description
Technical field
The present invention relates to field of medicaments, and the purposes in the drug for the treatment of flavivirus is prepared more particularly to a kind of compound.
Background technique
Dengue virus (dengue virus, DENV) belongs to flaviviridae, and Flavivirus (Flaviviridae), is to work as this life
It is distributed a kind of most wide arboviruse in boundary, dengue fever is mainly caused by the Aedes aegypti and aedes albopictus propagation that bite people,
In to there is dengue hemorrhagic fever/dengue shock syndrome (dengue hemorrhagic fever/dengue shock
Syndrome, DHF/DSS) it is even more serious.There are four serotypes for the virus, and 2 type of serum is popular diseased plant dengue fever (dengue
It fever) is the acute infectious disease propagated through mosquito matchmaker, mainly in tropical and subtropical region, prevalence is shown in figure one.It was sent out for the first time from 1779
Since existing dengue fever, Epidemic Situation of Dengue Fever has been broken out successively all over the world.Estimate according to WHO, the population in the whole world about 2/5 is by Dengue at present
The threat of heat, has the people of hundred million meters to infect the virus every year.In addition to there is prevalence in Taiwan, epidemic situation is concentrated mainly on extensively in China
East, mostly in outburst and Introduced cases prevalence feature, it is known that 4 kinds of serotype dengue virus be found in China, and in expansion
Dissipate the trend increased.Currently, the mechanism of dengue virus infection throw away it is indefinite, due to lack between each serotype it is effective intersect protect
Shield, but there are humidifications of antibody-dependant etc., and still available without safely and effectively vaccine so far, clinically there are no effectively control
Treat drug.Although having found many bioactive molecules for being directed to dengue fever virus major protein, (make for various reasons as poison is secondary
With the problems such as), there is presently no the drugs and vaccine that are directed to dengue fever virus, therefore, for the antiviral activity point of dengue fever
Son is found to have important biological study meaning and practice significance, provides branch to develop the active drug of dengue fever virus
It holds.
Currently, the mechanism of dengue virus infection is still indefinite, due to lacking effective cross protection between each serotype, again
There are humidifications of antibody-dependant etc., and still available without safely and effectively vaccine so far, clinically there are no effective medicines
Object.Although having found many bioactive molecules for being directed to dengue fever virus major protein, for various reasons (such as toxic side effect
Problem), there is presently no the drug listings for dengue fever virus.
Compound Bu Linibu Brivanib Alaninate of the present invention is a kind of ATP competition delivered for 2006
VEGFR2 inhibitor [Bhide, Rajeev S., et al. " the Discovery and preclinical studies of of property
(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo2,1-f1,2,
4triazin-6-yloxy)propan-2-ol(BMS-540215),an in vivo activepotent VEGFR-
2inhibitor."Journal of Medicinal Chemistry 49.7(2006):2143-6.].For the present invention relates to
Bu Linibu Brivanib Alaninate preparation treat or prevent 2 type dengue virus infection drugs in purposes belong to
First public, since framework types belong to completely new framework types, and it has well 2 type dengue fever virus inhibitory activity
Effect have substantive distinguishing features outstanding, while for stepping on there is no the possibility for providing any enlightenment due to other compounds
The treatment and prevention and treatment for removing from office fever virus infection obviously have significant progress, it is most likely that are developed to novel anti-dengue infection
Drug.
Summary of the invention
The purpose of the invention is to provide a kind of Brivanib Alaninate, i.e., compound shown in Formulas I is in conduct
Preparation treats or prevents the application in dengue virus infection drug, and Brivanib Alaninate is under 10.0 μM of concentration to 2 types
The inhibiting rate of dengue fever virus is 107.64%.And Brivanib Alaninate is under the conditions of 10.0 μM, to BHK-21 cell
Survival rate be 92.74%.Brivanib Alaninate can effectively inhibit the increment of dengue fever virus, be singly to cell
Toxicity very little can be further developed as the drug for the treatment of dengue virus infection, be with a wide range of applications.
The compound Brivanib Alaninate structure is shown in formula I:
Compound Brivanib Alaninate of the present invention is a kind of emulative VEGFR2 inhibitor of ATP, is
The pro-drug of Brivanib.2 type Dengues are treated or prevented in preparation for Brivanib Alaninate of the present invention
Purposes in fever virus infection medicine belong to it is first public, and its to 2 type dengue fever virus inhibitory activity have good effect
Fruit has substantive distinguishing features outstanding there is no the possibility for providing any enlightenment due to other compounds, while being used for dengue fever
The treatment and prevention and treatment of virus infection obviously have significant progress, it is most likely that are developed to the medicine of novel anti-dengue infection
Object.
One aspect of the invention provides compound shown in Formulas I or its drug acceptable salt and treats or prevents jaundice in preparation
Purposes in the drug of malicious viroid infection
Another aspect of the invention provides compound shown in Formulas I or its drug acceptable salt and steps in preparation treatment or prevention
Remove from office the purposes in the drug of virus infection.
In the inventive solutions, dengue virus is dengue virus 1-4 type.
In the inventive solutions, dengue virus is dengue type 2 virus.
Another aspect of the present invention provides compound shown in Formulas I or its drug acceptable salt and inhibits dengue virus in preparation
Purposes in the drug of middle NS3 and the mRNA of E protein.
Another aspect of the present invention provides compound shown in Formulas I or its drug acceptable salt and inhibits dengue virus in preparation
Purposes in the drug of middle NS3 and the protein expression of E protein.
Another aspect of the present invention provides a kind of pharmaceutical composition for treating dengue virus infection, contains as activity
Compound shown in the Formulas I of substance or its drug acceptable salt.
In this technical solution of the present invention, described pharmaceutical composition is ejection preparation, oral preparation or external preparation.
In the inventive solutions, described pharmaceutical composition is tablet, capsule, powder, pill, granule, note
Penetrate agent or emulsion.
Detailed description of the invention
Fig. 1 is the inhibiting effect of Brivanib Alaninate BHK-21 intracellular virus RNA metainfective to DENV2.
Fig. 2 is the inhibition of Brivanib Alaninate BHK-21 intracelluar toxalbumin synthesis metainfective to DENV2
Effect.
Fig. 3 is the inhibition work that Brivanib Alaninate BHK-21 cell metainfective to DENV2 generates progeny virus
With.
Specific embodiment
Toxicity test of the 1 Brivanib Alaninate of embodiment to BHK-21 cell:
BHK-21 cell (newborn hamster kidney cell) is the permissive cell of DENV2.BHK-21 cell in experiment is this department
It is all；MTT is purchased from green skies biotechnology research institute；Fetal calf serum is purchased from U.S. GIBICO company；Tissue culture plate is purchased from beauty
Corning Incorporated, state；1640 culture medium of RPMI is purchased from U.S. GIBICO company.
Experimental procedure is as follows:
1 inoculation BHK-21 cell: it is outstanding that individual cells are made into 1640 culture medium of RPMI containing 10% (V/V) fetal calf serum
Liquid, with 10000, every hole cell inoculation to 96 porocyte culture plates, every hole is inoculated with 100 μ l of volume
2 culture BHK-21 cells: at 37 DEG C, 5% (V/V) CO2It is cultivated 24 hours under condition of culture；
3 are added Brivanib Alaninate: inhaling the culture medium abandoned in each hole, 100 μ l are added with 10% to each hole
(V/V) 1640 culture medium of RPMI of fetal calf serum is diluted to the Brivanib Alaninate of respective concentration, and control wells are added not
1640 culture medium of RPMI, the 100 μ l of 10% (V/V) fetal calf serum of drug containing；
4 colour generations: after culture 48 hours, every hole adds 10 μ l of 5mg/mlMTT solution, at 37 DEG C, 5% (V/V) CO2Condition of culture
Under continue culture 4 hours, DMSO is then added, until under ordinary optical microscope observation discovery Formazan all dissolve；
5 measurements and calculating: absorption value is measured in 570nm, the cell under Brivanib Alaninate various concentration is deposited
Light absorption value of the motility rate for cell absorbance value under the concentration than upper control wells, multiplied by 100%.
Toxicity test of the Brivanib Alaninate of 1 various concentration of table to BHK-21 cell
The Brivanib Alaninate of the results show various concentration does not influence BHK-21 survival rate substantially, shows
It is low that the religion of Brivanib Alaninate toxicity is shown.
Inhibition test of the 2 Brivanib Alaninate of embodiment to DENV2:
It is the cell for cultivating virus DENV2,10TCID with BHK-2150, experimental procedure is as follows:
1 accesses BHK-21 in tissue culture plate, and cell is long to single layer after 24 hours, and the area of cell covering bottom hole is about
80%~90%, culture medium is sucked out, PBS is washed 1 time, and 200 μ l of access viral sample, 37 DEG C adsorb 1 hour.After the completion of absorption, inhale
The virus liquid in each hole is abandoned, PBS is cleaned 1 time.The diluted finger of 1640 culture medium of RPMI for containing 10% (V/V) fetal calf serum is added
The Brivanib Alaninate for determining concentration, in 37 DEG C of 5% (V/V) CO2It is cultivated under condition of culture.After 96 hours, cell occurs
After apparent cytopathy, supernatant is collected, surveys lactic dehydrogenase (LDH) content of cell release in supernatant；Or it cultivates to 48
After hour, cell conditioned medium is collected, virus plaque experiment is done；Or it cultivates to after 48 hours, the total mRNA of total protein points for collecting cell
Not Tong Guo detected by Western blot and real-time fluorescence quantitative PCR detect the content of intracelluar toxalbumin and the content of viral RNA.
2 survey the Dehydrogenase Content of cell release in supernatant: drawing 96 orifice plate cell conditioned medium, 120 μ l, use lactic dehydrogenase
It is cytotoxicity caused that enzyme citotoxicity detection kit (LDH Cytotoxicity Assay Ki, Beyotime) detects DENV institute
When the activity of lactic dehydrogenase that discharges.
Influence of the Brivanib Alaninate of 2 various concentration of table to the LDH of the DENV2 BHK-21 cell release infected
Experimental result: the experimental results showed that under 10 μM of concentration, Brivanib Alaninate leads to DENV2 infection
BHK-21 cell death there is very strong protective effect, inhibitory effect reaches 107.64%.And in the concentration, BHK-21
The survival rate of cell about 92.74%.
3 Brivanib Alaninate of embodiment inhibits test to the mRNA of DENV2 key protein NS3 and E protein
1 collects cell total rna: 1ml Trizol reagent (ambion) is added in the every hole of 6 porocyte culture plates, is placed at room temperature for 5
After minute, Aspirate supernatant to 1.5ml Eppendorf is managed；Every pipe adds 0.2ml chloroform, and concussion is incubated at room temperature 15 minutes, 4 DEG C
12000rpm is centrifuged 15 minutes, is drawn upper phase and is transferred to another 1.5mlEppendorf pipe；0.5ml isopropanol, shake is added
It swings, is incubated at room temperature 10 minutes, 4 DEG C of 12000rpm are centrifuged 10 minutes；It inhales and abandons supernatant, 75% (V/V) ethyl alcohol 1ml is added, washing is heavy
It forms sediment, 4 DEG C of 12000rpm are centrifuged 10 minutes, are inhaled and are abandoned supernatant；It dries at room temperature and is allowed to bleach；DEPC is added and handles 20 μ l of distilled water
RNA is dissolved, -80 DEG C save backup；260/280 absorbance ratio of UV spectrophotometer measuring calculates RNA concentration.
2 by RNA reverse transcription be cDNA: reaction system: RNA 1mg, 5 × PrimeScript RT MasterMix
(TAKARA) 4 μ l, the tri-distilled water that DEPC is handled to 20 μ l of total volume.It is careful mix after 37 DEG C of 15min, 85 DEG C 5 seconds.
3 real-time fluorescence quantitative PCRs detect the virus envelope protein of each sample and the rna level of non-structural protein 1: reaction
System (10 μ l): 1 μ l of cDNA template,QPCR Master Mix (Promega) 5 μ l, positive anti-primer 0.4 μ l, DEPC
The 3.2 μ l of tri-distilled water of processing.After mixing, 95 DEG C of 10 minutes initial denaturations, 95 DEG C 15 seconds, 60 DEG C 1 minute (40 circulation).
The positive anti-primer of each target RNA of table 3
4 calculate: calculating rna level of each sample relative to control group with 2- Δ Δ C т method according to the CT value of each sample.
Experimental result: referring to attached drawing 1, after Brivanib Alaninate processing, DENV2 key protein NS3 and E protein
MRNA level in-site significantly reduces, and has concentration dependent.Under 5 and 10 μM of concentration, NS3 and E protein are significantly reduced
MRNA level in-site.Show its ability with the duplication and the amplification that inhibit dengue virus.
4 Brivanib Alaninate of embodiment presses down the protein expression of DENV2 virus key protein NS3 and E protein
System test
1 collects total protein of cell: after BHK-21 cell drug and dengue virus (DENV2) processing, 48h leach protein:
Cold PBS washes cell, and RIPA lysate is added in the every hole of 6 orifice plates, and (inhibitors of phosphatases (Kai Ji is added in RIPA lysate (triumphant base biology)
Biology) and protease inhibitors (triumphant base biology)) every 100 μ l of hole, scraper, which scrapes, to be collected in 1.5ml Eppendorf and manages, and 4 DEG C
12000rcf is centrifuged 15min, shifts supernatant into new Eppendorf pipe.
2 test sample protein concentrations: protein standard substance is diluted to 0,0.0008,0.0016,0.0032 with distilled water,
0.004,0.006,0.008mg/ml gradient concentration；Protein standard substance and each 2.5 μ l of protein sample is taken to be added in 24 orifice plates,
1 × G250 working solution 1.5ml is added in every hole, makes every hole final volume 2.5ml, and room temperature is shaken 3 minutes, measures every hole with microplate reader
570nm extinction；The protein concentration in sample is calculated according to standard curve.Data are handled, the RIPA of respective volume is added in sample
Lysate keeps each sample protein concentration consistent with loading buffer.100 DEG C of denaturation 5min, -20 DEG C save backup.
3 protein immunoblots detect the expression of gradient concentration Brivanib Alaninate treated dengue virus albumen
Difference: the configuration of 10%SDS polyacrylamide gel: being sequentially added into various reagents, configures 10% separation gel rapidly in glass
The perfusion of glass gap, covers on separation gel rapidly the time needed for glue is concentrated in outflow perfusion (the about 0.8cm of lower edge below comb)
One layer of dehydrated alcohol removes dehydrated alcohol layer, is blotted with filter paper after glue polymerization to be separated, continues perfusion concentration glue, plugs comb
Son.Electrophoresis: powering on, and starting carries out electrophoresis with 80V constant pressure, after dye front enters separation gel, then is changed to 120V, according to
The separation degree of pre-dyed albumen Marker and the molecular weight of target protein determine electrophoresis time, general to run 75min or so.
4 transferring films: gel, the pvdf membrane of shear gel size are taken out from glass plate, and impregnates 1min in methyl alcohol, then use
Transfering buffering liquid (1*tris/glycine buffer, Biorad) impregnates 5min.By gel, filter paper, pvdf membrane, which is all immersed in, to be turned
In liquid relief, installing membrane-transferring device in the following order: cathode, -- -- -- -- -- filter paper -- cotton pad -- is just for pvdf membrane for gel for filter paper for cotton pad
Pole, above-mentioned article stack one by one, accurate alignment.Membrane-transferring device is placed in transferring film box, confirmation electrode is errorless, and transferring film liquid is added extremely
Entire membrane-transferring device is covered, transferring film box and top are covered with ice cube, powered on, 100V constant pressure transferring film 70min or so, are terminated
Afterwards, pvdf membrane is taken out.
5 protein blockings: pvdf membrane is placed in confining liquid, and room temperature shaker impregnates 1h, to close heterogenetic antigen.Closing
Afterwards, TBS/TT room temperature shaker is washed film 3 times, and each 5min is then incubated for primary antibody.
The hybridization of 6 primary antibodies: pvdf membrane albumen is placed in etui upwardly, is added and contains Dengue viral envelope albumen
(Dengue virus Envelope protein antibody, GeneTex) and non-structural protein 1 (Dengue virus
NS3glycoprotein antibody, abcam) primary antibody TBS/T configuration 5% (w/v) skim milk buffer, 4 DEG C are shaken
Bed is overnight.PBST room temperature shaker washes film six times, each 5min.
The hybridization of 7 secondary antibodies: pvdf membrane albumen is placed in etui upwardly, be added containing secondary antibody (rabbit-anti or mouse are anti-,
Proteintech 5% (w/v) skim milk buffer of TBS/T configuration), room temperature shaker 1 hour.PBST room temperature shaker is washed
Film six times, each 5min.
8 chemiluminescences development: it is uniformly added into ECL developer solution A/B liquid (CST) in proportion, pvdf membrane is immersed in luminescent solution
In, react 2min.Pvdf membrane is taken out, is placed in magazine, exograph is placed in darkroom exposure, and exposure takes out development, dries glue
Piece records, and saves.
Experimental result: referring to fig. 2, after Brivanib Alaninate processing, DENV2 key protein NS3 and E protein expression
Level significantly reduces, and is in concentration dependent.Under 5 and 10 μM of concentration, the expression of NS3 and E protein is significantly reduced,
With gene level result always.Showing it really has the function of inhibiting the expression of dengue virus key protein.
Plaque inhibition test of the 5 Brivanib Alaninate of embodiment to DENV2 virus
1 accesses C6/36 cell in 24 orifice plates, and to single layer, (cell covers the area of bottom hole about to cell length after 24 hours
90%~100%) culture medium abandoned in each hole, is inhaled, PBS is washed 1 time, the access diluted 200 μ l of viral sample of PBS, 37 DEG C of suctions
Attached 1 hour.
The supernatant in each hole is inhaled after the completion of 2 absorption and is abandoned, PBS washes away unadsorbed virus.It is added and contains 1.2% Methyl cellulose
1640 culture medium of RPMI of plain 2% (V/V) fetal calf serum, in 37 DEG C, 5% (V/V) CO2Incubator in culture it is 96~120 small
When.
3 inhale abandoning methylcellulose covering culture medium after plaque test is fixed with 4% paraformaldehyde (doctor's moral biology), then
With 1% (w/v) violet staining, crystal violet is washed away with flowing water after 2 hours, 24 orifice plates are scanned after drying, judged according to plaque number
Mol-5 BHK-21 cell metainfective to DENV2 generates the inhibiting effect of progeny virus.
Experimental result: referring to Fig. 3, viral plaque assay determines the quantity and infection energy of progeny virus after virus infection
Power.After handling as the result is shown, the progeny virus quantity and infection ability generated after DENV2 virus infection BHK-21 cell significantly drops
It is low.
SEQUENCE LISTING
<110>Nanfang Medical Univ
<120>drug and its pharmaceutical applications of the Bu Linibu as treatment dengue virus infection
<130> CP11901076C
<160> 6
<170> PatentIn version 3.3
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Claims (9)
1. compound shown in Formulas I or its drug acceptable salt are in the drug that preparation treats or prevents flavivirus virus infection
Purposes
2. the use of compound shown in Formulas I or its drug acceptable salt in the drug that preparation treats or prevents dengue virus infection
On the way.
3. purposes according to claim 2, wherein dengue virus is dengue virus 1-4 type.
4. purposes according to claim 2, wherein dengue virus is dengue type 2 virus.
5. the drug that compound shown in Formulas I or its drug acceptable salt inhibit NS3 and the mRNA of E protein in dengue virus in preparation
In purposes.
6. the protein expression that compound shown in Formulas I or its drug acceptable salt inhibit NS3 and E protein in dengue virus in preparation
Drug in purposes.
7. a kind of pharmaceutical composition for treating dengue virus infection, contain compound shown in the Formulas I as active material or its
Drug acceptable salt.
8. pharmaceutical composition according to claim 7, wherein described pharmaceutical composition be ejection preparation, oral preparation or
External preparation.
9. pharmaceutical composition according to claim 7, described pharmaceutical composition be tablet, capsule, powder, pill,
Granula, injection or emulsion.
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| CN201910110917.XA CN109602749B (en) | 2019-02-12 | 2019-02-12 | Britinib as medicine for treating dengue virus infection and pharmaceutical application thereof |
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| CN201910110917.XA CN109602749B (en) | 2019-02-12 | 2019-02-12 | Britinib as medicine for treating dengue virus infection and pharmaceutical application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115089591A (en) * | 2022-05-21 | 2022-09-23 | 复旦大学 | Application of brimonib in preparation of medicine for inhibiting enterovirus 71 type neurotropic virus |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106983736A (en) * | 2017-02-21 | 2017-07-28 | 南方医科大学 | Tatanan A are used as the medicine and its pharmaceutical applications for treating dengue virus infection |
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2019
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106983736A (en) * | 2017-02-21 | 2017-07-28 | 南方医科大学 | Tatanan A are used as the medicine and its pharmaceutical applications for treating dengue virus infection |
Non-Patent Citations (1)
| Title |
|---|
| SHERIF I.F. BADAWY等: ""Quality by design development of brivanib alaninate tablets:"", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115089591A (en) * | 2022-05-21 | 2022-09-23 | 复旦大学 | Application of brimonib in preparation of medicine for inhibiting enterovirus 71 type neurotropic virus |
| CN115089591B (en) * | 2022-05-21 | 2024-04-12 | 复旦大学 | Application of brinib in preparation of medicines for inhibiting enterovirus 71 type neurotropic viruses |
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