CN109864990A - Bali card replaces and is preparing the application in anti-filamentous virus infection medicine - Google Patents
Bali card replaces and is preparing the application in anti-filamentous virus infection medicine Download PDFInfo
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- CN109864990A CN109864990A CN201811272010.5A CN201811272010A CN109864990A CN 109864990 A CN109864990 A CN 109864990A CN 201811272010 A CN201811272010 A CN 201811272010A CN 109864990 A CN109864990 A CN 109864990A
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Abstract
The invention discloses Bali cards for the application in terms of anti-filamentous virus infection.The present invention includes that Bali card replaces the application in the prevention or treatment infected filamentous virus or the use in conjunction with other antiviral drugs.
Description
Technical field
The present invention relates to Bali cards to replace (Balicatib, CAS:354813-19-7) in terms of anti-filamentous virus infection
Using belonging to pharmaceutical technology field.The present invention includes that Bali card replaces answering in filamentous virus is prevented or treated alone or in combination
With.
Background technique
Filamentous virus belongs to filamentous virus section (Filoviridae), including three kinds of viruses: Ebola virus
(Ebolavirus, EBOV), Marburg virus (Marburgvirus, MARV), Kui watt virus (Cuevavirus, LLOV).Angstrom
Rich drawing virus and Marburg virus are control virus, are listed in A class bio-terrorism war agent, live virus needs are in bio-safety 4
Grade (P-4) laboratory operation completes [Centers for Disease Control and Prevention/National
Institutes of Health.Biosafety in Microbiological and Biomedical
Laboratories.4th ed.Washington,DC:U.S.Department of Health and Human
Services,U.S.Government Printing Office；1999.DHHS Publication CDC 93-8395.].
People can cause Ebola hemorrhagic fever and marburg hemorrhagic fever after infecting both viruses, and lethality can be respectively up to 90%
[Feldmann H,Geisbert TW.Ebola haemorrhagic fever.Lancet.2011；377(9768):849-
862.] and 80% [Knipe DM, Howley PM.Fields Virology, 6th Edition[M].Philadelphia:
Wolters Williams&Wilkins Health,2013:923-592].Kui watt virus was in the hole at Spain one in 2002
Be found in the bat body in cave, at present not yet clearly the virus whether can cause human diseases [Negredo A, Palacios G,
Vázquez-Morón S,et al.Discovery of an Ebolavirus-Like Filovirus in
Europe.PloS Pathogens,2011,7(10):e1002304]。
Filamentous virus is sub-thread minus-stranded rna virus, and genome length is about 19kb, and gene is successively sequentially 3'-NP-
VP35-VP40-GP-VP30-VP24-L-5' encodes viral surface glycoprotein GP and other 6 kinds of virus protein [Feldmann
H.Ebola-A Growing Threat? N Engl J Med 2014；371:1375-1378].EBOV points of 5 kinds of hypotypes: Zha Yi
Your type (Zaire-EBOV), the Sudan's type (Sudan-EBOV), Christopher Eccleston type (Reston-EBOV), Cote d'lvoire's type (
Forest-EBOV) and Ben Dibujiao type (Bundibugyo-EBOV), wherein Zaire's type lethal is most strong, up to 90%.It cuts
To currently, MARV and LLOV only have a kind of parting.Figure 10 is according to filamentous virus gene, using the silk of MEGA7 Software on Drawing
Shape viral gene evolution graph, wherein strain involved by this patent embodiment is marked with underscore,.
The membrane glycoprotein (Glycolprotein, GP) of filamentous virus is that filamentous virus is mediated to enter host cell only
One virus protein.GP amyloid protein precursor is cut by furin (Furin), generates two subunits of GP1 and GP2.GP1 is thin with host
Cellular surface specific receptor identifies and combines that then virus enters inclusion body by endocytosis and is transported to lysosome, in lysosome
Under acidic environment, GP2 allosteric and mediate retroviral cyst membrane and lysosome membrane are merged, and the inhereditary material of virus is finally made to be released into endochylema
[Takada A.Filovirus Tropism:CellularMolecules for Viral Entry.Frontiers in
Microbiology.2012；3:34.].Cell entry host cell is the first step of virus infection, find filamentous virus into
Enter inhibitor, it can effectively infection of the blocking virus to cell.
Ebola hemorrhagic fever and marburg hemorrhagic fever are acute infectious disease, and incubation period is 2-21 days, and Clinical symptoms is
Fever, myalgia, headache, sore-throat, vomiting, diarrhea, fash and hepatic and renal function are impaired, and hypotensive shock finally occurs in bleeding
Even dead [Streether LA.Ebola virus.Br J Biomed Sci.1999.56 (4): 280-284.].2014
West Africa broken out it is on the books since most serious Ebola epidemic situation, it is main at that time using isolation, symptomatic treatment and supportive to control
It treats, i.e. maintenance fluid and electrolyte balance, oxygen, blood pressure maintenance and treatment [Feldmann H, Geisbert to superinfection
TW.Ebola haemorrhagic fever.Lancet.2011.377 (9768): 849-862.], hereafter each state all pays close attention to simultaneously
Accelerate the medicament research and development process of anti-filamentous virus Hemorrhagic fever.Monoclonal antibody medicine ZMapp is researched and developed jointly by America & Canada, in
Enter II clinical trial phase within 2015.The assessment of convalescence blood plasma is in clinical II phase/III phase, small-molecule drug such as RNA polymerization
Enzyme inhibitor Favipiravir (T-705) also carry out at present to clinical II stage phase [Bixler SL, Duplantier AJ,
Bavari S.Discovering Drugs for the Treatment of Ebola Virus.Current Treatment
Options in Infectious Diseases.2017；9(3):299-317.].Said medicine is just for Ebola's bleeding
Heat, marburg hemorrhagic fever there is no curative drug at present.
Bali card is for the treatment osteoporosis in postmenopausal women drug for being Novartis Co., Ltd's research and development.Its oral tolerance is good,
But in II clinical trial phase, occur sclerosis of the skin after subject is oral 50mg/ days continuous 9 months, therefore the medicament research and development
Terminate [Chappard D, Libouban H, Mindeholm L, et al.The Cathepsin K inhibitor
AAE581induces morphological changes in osteoclasts of treated
patients.Microscopy Research and Technique.2010；73(7):726–732.].After postmenopausal women by
Bone metabolism can be caused unbalance in decrease in estrogen, i.e. bone reabsorption is greater than ostosis, and whole body bone amount is caused to reduce and cause bone
Matter osteoporosis seriously affects quality of life [Bossard MJ, Tomaszek TA, Levy MA, et al.Mechanism of
Inhibition of Cathepsin K by Potent,Selective 1,5-Diacylcarbohydrazides:A New
Class of Mechanism-Based Inhibitors of Thiol Proteases.Biochemistry,1999,38
(48),pp 15893–15902].Bali card passes through for the inhibitor for being cathepsin K and inhibits osteoclast Type I collagen drop
It solves and inhibits the excessive reabsorption of bone.By literature search, it has no about Bali card for anti-filamentous virus (including Ebola virus, horse
Your fort virus, Kui watt virus) activity or any antiviral activity report.
The present invention is to find Bali based on evaluating grinding drug using Ebola virus infection model various clinical
Card, which replaces, can block EBOV to infect host cell.Research also shows that Bali card is replaced to Marburg virus and Kui Wa virus infected cell
Also there is inhibitory activity.Accordingly it is considered that Bali card is for being anti-filamentous virus broad spectrum inhibitors, has and be applied to treatment filiform
Virus causes the potential applicability in clinical practice of Hemorrhagic fever.The present invention relates to the patents of invention of existing new medicine use.
Summary of the invention
Present invention solves the technical problem that being to provide, Bali card is replaced and its pharmaceutically acceptable salt prevents or controls in preparation
Treat the application in the drug of filamentous virus infection.
Specifically, being adopted the following technical scheme that solve technical problem of the invention
There is provided the Bali cards as shown in structure formula (I) to replace and its pharmaceutically may be used for the first aspect of technical solution of the present invention
Application of the salt of receiving in preparation prevention or treatment filamentous virus drug
The pharmaceutically acceptable salt that the Bali card replaces, including pharmaceutically acceptable organic salt or inorganic salts,
In, the organic salt includes sulfonate, carboxylate, amino-acid salt and fatty acid salt, and inorganic salts include hydrochloride, bromic acid
Salt, iodate, sulfate, disulfate, phosphate, hydrophosphate, dihydric phosphate and nitrate.Preferably disulfate,
Sulfate, hydrochloride and iodate.
The sulfonate includes alkylsulfonate and benzene sulfonate, tosilate, neighbour containing 1-15 carbon atom
Toluene fulfonate, m-toluene sulfonic acid salt；Carboxylate includes tartrate, maleate, fumarate, citrate, malic acid
Salt, cinnamate, benzoate, malonate, succinate, glutarate, adipate, embonate and lactate；
Amino-acid salt includes glutamate, aspartate；Fatty acid salt includes the hard soap containing 2-18 carbon atom.
The second aspect of technical solution of the present invention provides a kind of pharmaceutical composition in preparing anti-filamentous virus drug
It include that Bali card shown in structure formula (I) replaces and its pharmaceutically acceptable using, which is characterized in that the pharmaceutical composition
Salt and pharmaceutically acceptable carrier or excipient；The pharmaceutical composition can also contain other antiviral agents
The pharmaceutical composition can be prepared according to method well known in the art.It can be by by the compounds of this invention and a kind of or more
The pharmaceutically acceptable solid of kind or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle
Or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin,
Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder-injection
And infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge,
Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis), granule, dissipate
Agent, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel
Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made,
Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute
Release agent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, cream
Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second
Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum
Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card
Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber
Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second
Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin
Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet
Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphate, acetate, hydrochloric acid, hydrogen
Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder
Mannitol, glucose etc. can be also added as proppant in injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
The inventors found that Bali card infects host cell for blocking filamentous virus that can be specific.Can also and
Other antiviral drugs carry out drug combination.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
Filamentous virus described in first aspect present invention and second aspect includes but is not limited to Ebola virus, Marburg disease
Poison, Kui watt virus.
The Ebola virus includes but is not limited to Zaire's type, the Sudan's type, Christopher Eccleston type, Cote d'lvoire's type and Ben Di
Cloth coke type.
Advantageous effects
Bali card replaces II clinical trial phase in osteoporosis in postmenopausal women, and its tolerance is good as the result is shown, Huan Zhelian
Only there is the adverse reaction of sclerosis of the skin within continuous oral 50mg/ days 9 months, lesion disappears and do not recur in two years after drug withdrawal.Due to
The filamentous virus Hemorrhagic fever course of disease is shorter, and relative to filamentous virus Hemorrhagic fever is highly pathogenic and high lethality rate, the pair that Bali card replaces
It acts on very slight, it is believed that Bali card is high for the new application clinical value of anti-filamentous virus, and confirmation Bali card replaces anti-filiform
The new application of virus can make it be quickly applied to high-risk viral infection, alleviate epidemic situation.
Detailed description of the invention
Fig. 1 Bali card is for blocking Mayinga plants of infection activities of Zaire's type Ebola virus.
Fig. 2 Bali card is for blocking Makona plants of infection activities of Zaire's type Ebola virus.
Fig. 3 Bali card is for blocking the Sudan's type Ebola virus infection activity.
Fig. 4 Bali card is for blocking Cote d'lvoire's type Ebola virus infection activity.
Fig. 5 Bali card is for blocking Christopher Eccleston type Ebola virus infection activity.
Fig. 6 Bali card is for blocking Ben Dibujiao type Ebola virus infection activity.
Fig. 7 Bali card is for Marburg virus Musoke plants of infection activity of blocking.
Fig. 8 Bali card is for Marburg virus Ravn plants of infection activity of blocking.
Fig. 9 Bali card is for blocking Kui watt viral infectivity.
Figure 10 filamentous virus phylogenetic trees (strain involved by this patent embodiment is marked with underscore).
Specific embodiment
Embodiment Bali card is for anti-filamentous virus activity
1. the principle of screening model
Filamentous virus enters the first step that host cell is virus infection, inhibits the entrance of virus can effectively blocking virus sense
Dye.The glycoprotein (Glycoprotein, GP) on filamentous virus cyst membrane surface is the key protein that filamentous virus enters process.
Invention applies filamentous virus coating GP genes, including Mayinga plants of coating GP of Zaire type Ebola virus
Gene (EBOV-Mayinga GP, Gene Accession No.L11365), Makona plants of coatings of Zaire type Ebola virus
GP gene (EBOV-Makona GP, Gene Accession No.KJ660346.2), the Sudan's type Ebola virus envelope GP base
Because of (EBOV-Sudan GP, Gene Accession No.FJ968794.1), Cote d'lvoire's type Ebola virus envelope GP gene
(EBOV-Forest GP, Gene Accession No.FJ217162.1), Christopher Eccleston type Ebola virus envelope GP gene
(EBOV-Reston GP, Gene Accession No.U23152.1), Ben Dibujiao type Ebola virus envelope GP gene
(EBOV-Bundibugyo GP, Gene Accession No.KR063673.1)；Musoke plants of coating GP bases of Marburg virus
Because of (MARV-Musoke GP, Gene Accession No.DQ217792.1), Ravn plants of coating GP genes of Marburg virus
(MARV-Ravn GP,Gene Accession No.DQ447649.1)；Kui watt peplos GP gene (LLOV GP, Gene
Accession No.JF828358.1).Pass through cotransfection GP albumen plasmid and pNL4-3-Luc-R-E-, can get filamentous virus
GP is Ebola's recombinant virus EBOV-GP/HIV [Lennemann NJ, the Rhein BA, Ndungo that shell wraps up HIV core
E, et al.Comprehensive analysis of ebola virus GP1in viral entry.J Virol.2005；
79:4793-805.], including Mayinga-GP/HIV, Makona-GP/HIV, Sudan-GP/HIV, Forest-GP/
HIV, Reston-GP/HIV, Bundibugyo-GP/HIV；Marburg recombinant virus MARV-GP/HIV [Manicassamy B1,
Wang J,Rumschlag E,et al.Characterization of Marburg virus glycoprotein in
viral entry.Virology.2007；358:79-88], including Musoke-GP/HIV, Ravn-GP/HIV；Kui Wa recombination disease
Malicious LLOV-GP/HIV [Maruyama J, Miyamoto H, Kajihara M, et al.Characterization of the
Envelope Glycoprotein of a Novel Filovirus,Lloviu Virus.Journal of
Virology.2014；88(1):99-109.doi:10.1128/JVI.02265-13.].Above-mentioned virion has following spy
Point: 1) virus depends on the characteristic of GP to the selectivity of host cell；2) due on HIV carrier env, nef and vpr gene lack
It loses, therefore the virus can only disposably enter host cell and not reproducible, so the virus is safe；3) HIV is carried
A luciferase reporter gene, therefore infected cell meeting expressing luciferase are had on body, are passed through and are detected luciferase
The degree that activity is infected with regard to signable cell.
2. experimental method and result
Following Strain is applied in the present invention, and pharmacological activity evaluation is carried out for the infection of anti-filamentous virus to Bali card: angstrom
It is rich to draw virus: EBOV-Mayinga (Gene Accession No.L11365), EBOV-Makona (GeneAccession
No.KJ660346.2), EBOV-Sudan (Gene Accession No.FJ968794.1), EBOV- Forest(Gene
Accession No.FJ217162.1), EBOV-Reston (Gene AccessionNo.U23152.1), EBOV-
Bundibugyo(Gene Accession No.KR063673.1)；Marburg virus: MARV-Musoke (Gene
Accession No.DQ217792.1), MARV-Ravn (Gene Accession No.DQ447649.1)；Kui watt virus:
LLOV(Gene Accession No.JF828358.1)。
Recombinant virus prepares [Chen Q, Tang K, Zhang XY, et al.Establishment of
pseudovirusinfection mouse models for in vivo pharmacodynamics evaluation of
filovirus entryinhibitors.Acta Pharmaceutica Sinica B(2017),http://
Dx.doi.org/10.1016/j.apsb.2017.08.003]: 2 μ g pcDNA3.1/EBOV-Mayinga GP plasmid of cotransfection
With 2 μ g pNL4-3-Luc-R-E-Plasmid is to 293T cell, and 48h collects supernatant after transfection, supernatant through 0.45 μm of membrane filtration,
Contain Mayinga-GP/HIV virion in filtrate, which can be used for infecting.Ebola is prepared according to same method
Recombinant virus: Makona-GP/HIV, Sudan-GP/HIV,Forest-GP/HIV, Reston-GP/HIV,
Bundibugyo-GP/HIV；Marburg recombinant virus: Musoke-GP/HIV, Ravn-GP/HIV；Kui watt recombinant virus: LLOV-
GP/HIV virion.
Infect [Chen Q, Tang K, Zhang XY, et al.Establishment of pseudovirus
infectionmouse models for in vivo pharmacodynamics evaluation of filovirus
entry inhibitors.Acta Pharmaceutica Sinica B(2017),http://dx.doi.org/10.1016/
J.apsb.2017.08.003]: infection the previous day, by every hole 6 × 104The density of a cell is by 293T cell inoculation to 48 orifice plates
On.Test-compound is dissolved with DMSO.Test-compound was added in cell culture fluid in infection first 15 minutes, with DMSO solvent work
Then virus liquid infection cell is added in blank control.It after infection 48 hours, discards supernatant, is then infected in cell to every hole
50 μ l cell pyrolysis liquid (Promega) lytic cells are added, by 30 μ l luciferase substrates (Promega) and 20 μ l cell crackings
After liquid mixing and with the relative activity (Relative of FB15 fluorescence detector (Sirius) Instrument measuring cell fluorescence element enzyme
Luciferase Units, RLUs), the level of the infection of active reaction virus.The work of the anti-filamentous virus of test-compound
Property indicates with inhibiting rate, inhibiting rate (%)=(RLUsSolvent control-RLUsDrug to be measured)/RLUsSolvent control×100.The results show that Bali card
For infection of the filamentous virus to host cell can be effectively suppressed, 1-3 the results are shown in Table, amount effect curve is shown in Fig. 1-9.
1 Bali card of table replaces anti-Ebola's recombinant virus (EBOV-GP/HIV) infection activity
2 Bali card of table replaces anti-Marburg recombinant virus (MARV-GP/HIV) infection activity
3 Bali card of table replaces anti-Kui watt recombinant virus (LLOV-GP/HIV) infection activity
Claims (7)
1. the Bali card as shown in structure formula (I) replaces and its pharmaceutically acceptable salt is in preparation prevention or treatment filamentous virus sense
Application in the drug of dye,
2. application according to claim 1, which is characterized in that the pharmaceutically acceptable salt, including it is pharmaceutically acceptable
Organic salt or inorganic salts, wherein the organic salt includes sulfonate, carboxylate, amino-acid salt and fatty acid salt, inorganic
Salt includes hydrochloride, bromate, iodate, sulfate, disulfate, phosphate, hydrophosphate, dihydric phosphate and nitric acid
Salt.
3. application according to claim 2, which is characterized in that the sulfonate includes the alkyl sulfonic acid containing 1-15 carbon atom
Salt, benzene sulfonate, tosilate, o-toluene sulfonic acid salt, m-toluene sulfonic acid salt；Carboxylate includes tartrate, maleic acid
Salt, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, oneself
Diacid salt, embonate and lactate；Amino-acid salt includes glutamate, aspartate；Fatty acid salt includes containing 2-18
The hard soap of a carbon atom.
4. a kind of application of pharmaceutical composition in the drug of preparation prevention or treatment filamentous virus infection, which is characterized in that institute
The pharmaceutical composition stated is replaced comprising Bali card shown in structure formula (I) and its pharmaceutically acceptable salt, and can pharmaceutically connect
The carrier or excipient received
5. application according to claim 4, which is characterized in that the pharmaceutical composition also contains other antiviral agents.
6. any one of -4 application according to claim 1, which is characterized in that the filamentous virus includes Ebola virus, horse
That fort virus, Kui watt virus.
7. application according to claim 6, which is characterized in that the Ebola virus includes Zaire's type, the Sudan's type, Lai Si
Pause type, Cote d'lvoire's type and Ben Dibujiao type.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125893A (en) * | 2020-09-15 | 2020-12-25 | 中山大学 | Small molecule compound with anti-filovirus function and application thereof |
| WO2023132842A1 (en) * | 2022-01-10 | 2023-07-13 | AiPharma Global Holdings LLC | Drug combination to treat microbial infections including coronavirus |
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| CN103687593A (en) * | 2011-05-16 | 2014-03-26 | 拜耳知识产权有限责任公司 | Use of cathepsin k inhibition for the treatment and/or prophylaxis of pulmonary hypertension and/or heart failure |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103687593A (en) * | 2011-05-16 | 2014-03-26 | 拜耳知识产权有限责任公司 | Use of cathepsin k inhibition for the treatment and/or prophylaxis of pulmonary hypertension and/or heart failure |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125893A (en) * | 2020-09-15 | 2020-12-25 | 中山大学 | Small molecule compound with anti-filovirus function and application thereof |
| WO2023132842A1 (en) * | 2022-01-10 | 2023-07-13 | AiPharma Global Holdings LLC | Drug combination to treat microbial infections including coronavirus |
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