CN115501234B - Application of compound in preparing medicine for preventing and treating demyelinating diseases - Google Patents
Application of compound in preparing medicine for preventing and treating demyelinating diseases Download PDFInfo
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Abstract
The invention provides application of a compound in preparing a medicament for preventing and treating demyelinating diseases. The compounds of formulas I-V of the present invention can promote the differentiation and myelination of oligodendrocyte precursor cells into oligodendrocytes by inhibiting TM7SF2 to enhance the accumulation of FF-MAS in cholesterol metabolic pathways; promoting the differentiation of original oligodendrocyte precursor cells to oligodendrocyte cells in the brain of a patient with demyelinating disease, forming myelin re-wrapping axons, recovering the neural function decline caused by loss of myelin sheath, and having the effects of treating and/or alleviating and/or preventing demyelinating disease.
Description
The application is a divisional application of application number 202110880211.9 and application of application date 2021, month 08 and 02, and the invention name is application of a compound in preparing medicines for treating and/or preventing demyelinating diseases.
Technical Field
The invention belongs to the technical field of new application of compounds, and particularly relates to application of a compound in preparation of a medicament for preventing and treating demyelinating diseases.
Background
In the vertebrate central nervous system (Central nervous system, CNS), axonal myelination effects nerve impulse skip conduction, accelerating nerve impulse conduction velocity. Oligodendrocytes (OL) and Schwann cells (Schwann cells) produce myelin sheaths of the central and peripheral nervous systems (peripheral nervous system, PNS), respectively. Among them, OL is produced by the differentiation of oligodendrocyte precursor cells (oligodendrocyte precursor cell, OPC). Multiple demyelinating diseases such as multiple sclerosis (Multiple sclerosis, MS), guillain-Barre syndrome (Guillain-Barre syndrome), neuromyelitis optica (Neuro myelitis optica, NMO) cause damage and loss of myelin sheath of the nerve axon, which in turn causes impaired neurological function. Normally, adult human brain stores OPC can be recruited to migrate to the focal area and differentiate into OL, thereby creating myelin around axons. However, under pathological conditions, this process is hindered. Current therapies targeting the immune system can reduce immune-mediated damage in demyelinating diseases, but fail to promote remyelination and repair of nerve axons.
The main component of the myelin sheath is lipid, accounting for about 70% of dry weight, which can protect axons and realize nerve impulse jump conduction, and accelerate nerve signal conduction speed. Oligodendrocyte precursor cells are present in the brain of adult individuals, but under pathological conditions of demyelinating diseases, oligodendrocyte precursor cells in the brain are difficult to autonomously differentiate into oligodendrocytes and produce myelin. Thus, there is a need to find new compounds that promote oligodendrocyte precursor cell differentiation.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. For this reason, the first aspect of the present invention proposes the use of a compound or a derivative thereof for the preparation of a medicament for the treatment and/or prevention of demyelinating diseases, which is capable of effectively treating and/or preventing demyelinating diseases.
In a second aspect, the invention provides a pharmaceutical composition for the treatment and/or prophylaxis of demyelinating diseases.
According to a first aspect of the present invention, there is provided the use of a compound of the following formulae I to V or derivatives thereof for the manufacture of a medicament for the treatment and/or prophylaxis of demyelinating diseases:
wherein, the CAS number of the compound of formula I is 2096197-23-6, and the chemical name is: 3- (3, 5-dimethyl-1H-pyrazol-1-yl) -N- ({ 1-oxo-2- [ (pyridin-3-yl) methyl ] -1H,2H,3H, 4H-pyrrole [1,2-a ] pyrazin-3-yl } methyl) propanamide (3- (3, 5-dimethyl-1H-pyrazol-1-yl) -N- ({ 1-oxo-2- [ (pyridin-3-yl) methyl ] -1H,2H,3H, 4H-pyrroo [1,2-a ] pyrazin-3-yl } methyl) propenamide); the CAS number for the compound of formula II is 1775503-94-0, chemical name 1- [ (2, 3-dihydro-1-benzofuran-5-yl) methyl ] -4- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl ] -N-methylpyrrolidine-3-carboxamide (1- [ (2, 3-dihydro-1-benzofuran-5-yl) methyl ] -4- [3- (methoymethyl) -1,2, 4-oxazol-5-yl ] -N-methylpyrrolidine-3-carboxamide); the CAS number for the compound of formula III is 686301-37-1, chemical name: 5- (2- {6-amino-9- [ (2 s,3s,4r,5 s) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl ] -9H-purin-8-yl } hydrazino-1-ylidene) -1, 3-diazinon-2, 4,6-trione (5- (2- {6-amino-9- [ (2 s,3s,4r,5 s) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl ] -9H-prin-8-yl } hydro-zin-1-yl) -1, 3-diazine-2, 4, 6-trione; CAS number of formula IV: 714914-49-5, chemical name: 1,1'- (1, 2-phenylenedi (methylene)) bis (5-methylpyrimidine-2, 4 (1 h,3 h) -dione) (1, 1' - (1, 2-phenylenebis (methylene)) bis (5-methylpyrimidine-2, 4 (1 h,3 h) -dione)); the CAS number for the compound of formula V is 931589-90-1, chemical name: 2- [ [2,3,6,7-tetrahydro-7- [2- (4-methoxyphenyl) ethyl ] -1,3-dimethyl-2,6-dioxo-1H-purin-8-yl ] thio ] -butyric acid (2- [ [2,3,6, 7-tetrahydroo-7- [2- (4-methoxyphenyl) ethyl ] -1,3-dimethyl-2,6-dioxo-1H-purin-8-yl ] thio ] -bunaneoid acid).
In the present invention, the compounds of formula I-formula V enhance the accumulation of FF-MAS (Follicular Fluid Meiosis-activating Sterol, cumulus cells secreting meiosis sterols, CAS number 64284-64-6) in the cholesterol metabolic pathway by inhibiting TM7SF2, and the accumulation of FF-MAS can promote oligodendrocyte precursor cell differentiation and myelination to oligodendrocytes.
In some embodiments of the invention, the derivatives include pharmaceutically acceptable salts, esters, hydrates, solvates, crystalline forms, enantiomers, stereoisomers, ethers, metabolites and prodrugs thereof.
In some preferred embodiments of the present invention, the pharmaceutically acceptable salts include, but are not limited to, at least one of inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates; preferably, the inorganic acid salts include, but are not limited to, at least one of hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; preferably, the organic acid salt includes, but is not limited to, at least one of formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, and citrate; preferably, the alkyl sulfonates include, but are not limited to, at least one of methyl sulfonate and ethyl sulfonate; the arylsulfonate includes, but is not limited to, at least one of benzenesulfonate and p-toluenesulfonate.
In some more preferred embodiments of the invention, the agent for treating and/or preventing demyelinating diseases is an agent that promotes remyelination.
In some more preferred embodiments of the invention, the agent that promotes remyelination is an agent that promotes oligodendrocyte precursor cell differentiation maturation or promotes expression of myelin-associated protein.
In some more preferred embodiments of the present invention, the agent for treating and/or preventing demyelinating diseases is a pharmaceutical composition having any one of the compounds of formulas I to V as the sole active ingredient or comprising at least one of the compounds of formulas I to V.
In some more preferred embodiments of the present invention, the amount of any one of the compounds of formulas I to V in the agent for treating and/or preventing demyelinating diseases is 0.1 to 99wt%; preferably 1 to 90wt%; further preferably 10 to 85wt%.
In some more preferred embodiments of the present invention, the medicament for treating and/or preventing demyelinating diseases is a decoction, a powder, a pill, a medicated wine, a lozenge, a gel, a plaster, a tea, qu Ji, a cake, a lotion, a stick, a wire, a strip, a nail, a moxibustion plaster, a paste, a pellet, a microcapsule, an intravenous emulsion, a liposome preparation, an aerosol, a prodrug preparation, an injection, a mixture, an oral ampoule, a tablet, a capsule, a drop pill, an emulsion, an ointment, a rubber plaster, a film, a sponge, an iontophoresis agent, a transdermal absorber.
According to a second aspect of the present invention, a pharmaceutical composition for the treatment and/or prevention of demyelinating diseases is provided, comprising at least one compound of formula I to formula V or a derivative thereof and a pharmaceutically acceptable adjuvant.
The beneficial effects of the invention are as follows: the compounds of formulas I-V of the present invention can promote the differentiation and myelination of oligodendrocyte precursor cells into oligodendrocytes by inhibiting TM7SF2 to enhance the accumulation of FF-MAS in cholesterol metabolic pathways; promoting the differentiation of original oligodendrocyte precursor cells to oligodendrocyte cells in the brain of a patient with demyelinating disease, forming myelin re-wrapping axons, recovering the neural function decline caused by loss of myelin sheath, and having the effects of treating and/or alleviating and/or preventing demyelinating disease.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a graph showing the quantitative effect of the compounds of formulas I to V according to the present invention on the promotion of oligodendrocyte precursor cell differentiation.
FIG. 2 shows the immunofluorescence results of the compounds of formulas I-V according to the invention with DMSO negative controls on oligodendrocyte precursor cell differentiation, on a scale of 100. Mu.m.
FIG. 3 shows Western blotting of oligodendrocyte precursor cell differentiation by using the compounds of formulas I-V according to the present invention.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Examples
Promotion of Oligodendrocyte Precursor Cell (OPC) differentiation by Compounds of formulas I-V
The experimental method comprises the following steps:
in order to study and confirm the effect of the compounds of the formulas I to V on OPC differentiation, the compounds of the formulas I to V are verified to promote OPC differentiation and maturation.
Experimental cells: primary cultured Oligodendrocyte Precursor Cells (OPC).
Experimental drugs and antibodies:
the medicine of the invention: compounds of formula I-V
Negative control drug: DMSO (DMSO)
Positive control drug: thyroxine 3 (T) 3 )
Cell culture: removing neck to kill ICR pregnant mice of E14.5, cleaning abdomen with alcohol cotton ball, dissecting, separating uterus, sequentially soaking with 75% alcohol and PBS, transferring to 60mm dish containing appropriate amount of HBSS, and transferring to biosafety cabinet; fetal mice were isolated from the uterus under dissecting microscope using forceps and surgical scissors. Forceps were used to tear open the brain skin/skull, remove the olfactory bulb, cerebellum and basal nuclei, and transfer the remaining brain cortex to a new 60mm dish containing NPC medium. Forceps cut off head, extremities, tail and viscera, and trunk was transferred to a 60mm dish additionally containing cold PBS for MEF extraction; all cerebral cortex was cut into 1mm with surgical scissors 3 The pellet was gently blown by a pipette, filtered through a 40 μm sieve, centrifuged at 1000rpm for 5min, the supernatant was discarded, resuspended in an appropriate amount of NPC medium, transferred to 100mm dishes for suspension culture (3 cells extracted from the fetal mice were cultured on average in each dish), counted as P0 generation, cultured for 2-3 days or the neurosphere diameter reached 100 μm for passaging.
OPC differentiation experiment: the P5 generation neurospheres are digested into single cells by Ackutase enzyme according to the specification of 4 multiplied by 10 4 Cell/pore density was seeded into 96-well plates (pre-multimerized ornithine and Laminin coating) and OPC medium was cultured for 2 days to induce differentiation of NPC into OPC; discarding OPC medium, washing with DPBS for 1 time, changing to OL medium, adding 0.05 μM, 0.1 μM, 1 μM, 20 μM of compound of formula I-formula V, respectively, and differentiating OPC into OL 3 days after 96-well plate negative control (DMSO, 0.2%, V/V) and positive control (T3, 100 nM); subjecting the differentiated cells to 4%PFA fixation, MBP (myelin basic protein, myelin basic protein, MBP) immunofluorescent staining; the staining results were imaged with Scan-R using a high content imaging system, and MBP+ cell percentages were used as indicators, and DMSO negative control was selected as the standard, with MBP+ cell ratios higher than this standard to promote OPC differentiation.
Protein extraction and immunoblot analysis:
the P5 generation neurospheres were digested with Ackutase enzyme to form single cells according to 1.2X10 6 Cell/well density was seeded into 6-well plates (pre-coated with polyornithine and Laminin). Extracting protein after two days of OPC differentiation and three days of OL differentiation according to the differentiation method; the medium was discarded and DPBS was washed 1 time. 150 mu L/hole RAPI lysate is added, and the mixture is kept stand for 30min at 4 ℃; the protein concentration was determined using BCA kit by scraping the supernatant, collecting the supernatant, centrifuging at 14000rpm at 4℃for 15 min. Adding instant protein loading buffer (denaturation, reduction, 5×), heating at 100deg.C for 10min to denature protein, and storing at-20deg.C or immediately using.
Preparing 12% separating gel, adding TEMED, and shaking. Pouring into a glass plate, adding deionized water for liquid sealing, and standing at room temperature for 30min for solidification; deionized water was discarded, concentrated gum (TEMED added) was added, and then a comb was inserted to ensure no air bubbles were generated and left to set at room temperature for 20 min. Washing the gel plate, placing into an electrophoresis tank, adding enough electrophoresis liquid, pulling out the comb, and adding 10 mu L and 5 mu LM marker respectively. Protein samples were added in between. Each group of samples 1 was added at 15 μl and the other samples in the same group were added at a ratio calculated from absorbance values measured using BCA kit. And (3) carrying out 120V constant pressure for 20min, and carrying out band electrophoresis until the separation gel and the concentrated gel are separated. And then 100V electrophoresis is carried out for 40min-60min to Marker full development. PVDF film with proper size is cut, immersed in methanol and activated for 5min. Adding a proper amount of film transfer liquid to the tray, and immersing the filter paper and the foam cushion into the film transfer liquid; and (5) prying the rubber plate to remove the concentrated rubber and the redundant separating rubber around. Placed on a filter paper. Opening a clamp for transferring the membrane, placing according to the black surface, the foam-rubber cushion, the filter paper, the glue, the PVDF membrane, the filter paper, the foam-rubber cushion and the white surface, and clamping the clamp; and placing the clamp into a film transfer groove, wherein the black surface of the clamp corresponds to the black surface of the film transfer groove, and the white surface corresponds to the red surface of the film transfer groove. Pouring a proper amount of film transfer liquid, and placing two small ice boxes into the film transfer groove. And then placed in ice. 300mA film transfer for 1.5h.
Taking out PVDF film from the film transferring groove, adding proper amount of 5% skimmed milk powder, shaking at room temperature and sealing for 2h; discarding 5% skimmed milk powder, and washing with TBST for 3 times each for 10min; adding a proper amount of primary antibody, and incubating overnight at 4 ℃; sucking the primary antibody away, and washing with TBST for 3 times, each time for 10min; adding a proper amount of secondary antibody (diluted by 2.5% skimmed milk powder), and incubating for 2h at room temperature by shaking; sucking away the secondary antibody, and washing with TBST for 3 times, each time for 10min; luminescent development imaging: ECL enhanced chemiluminescent liquid A and ECL enhanced chemiluminescent liquid B are mixed in equal volume and uniformly dripped on a film, and the film is subjected to exposure imaging by an instrument.
The results are shown in FIGS. 1 to 3, where "..times" in FIG. 1 is denoted as P<0.01, "" represents P<0.001, "" is represented by P<0.0001, when P<At 0.01, there was a significant difference between the groups compared to the negative control group, 0.2% dmso group. As can be seen, MBP (oligodendrocyte maturation expressed protein) positive cell rate (MBP) of formulas I-V + In%) and the concentration of the compound, wherein 0.05. Mu.M formula I, 0.1. Mu.M formula II, 0.1. Mu.M formula III, 0.1. Mu.M formula IV and 1. Mu.M formula V have the best MBP positive cell rate, i.e.the best activity to promote oligodendrocyte differentiation, compared to the negative control.
In FIG. 2, blue is shown as nuclei (stained with DAPI), red is shown as MBP, and scale is 100 μm, and it can be seen that the MBP expression level of formulas I-V is significantly increased compared to the negative control group 0.2% DMSO group, which directly proves that formulas I-V can promote oligodendrocyte precursor cell differentiation and maturation at corresponding concentrations.
As can be seen from FIG. 3, according to the expression level of MBP protein, the MBP expression of the formula I-formula V is higher than that of the negative control group by 0.2% DMSO group, namely the formula I-formula V promotes the MBP expression, which indicates that the formula I-formula V can promote the differentiation and maturation of oligodendrocyte precursor cells.
While the embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (7)
1. Use of a compound of formula III or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of demyelinating diseases:
。
2. the use according to claim 1, characterized in that: the medicament for treating and/or preventing demyelinating diseases is a medicament for promoting remyelination.
3. The use according to claim 2, characterized in that: the medicament for promoting remyelination is a medicament for promoting the differentiation and maturation of oligodendrocyte precursor cells or promoting the expression of myelin-associated proteins.
4. The use according to claim 1, characterized in that: the medicine for treating and/or preventing demyelinating diseases takes the compound of the formula III as the only active ingredient or comprises a medicine composition of the compound of the formula III.
5. The use according to claim 1, characterized in that: the content of the compound shown in the formula III in the medicament for treating and/or preventing demyelinating diseases is 0.1-99wt%.
6. The use according to claim 1, characterized in that: the content of the compound in the formula III in the medicament for treating and/or preventing demyelinating diseases is 1-90 wt%.
7. The use according to claim 1, characterized in that: the medicine for treating and/or preventing demyelinating diseases is decoction, powder, pill, medicated wine, lozenge, colloid, medicinal tea, qu Ji, cake, lotion, stick, line, strip, nail, moxibustion agent, paste, pill, liposome preparation, aerosol, injection, mixture, tablet, capsule, dripping pill, emulsion, membrane, sponge, iontophoresis agent, and transdermal absorbent.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211173846.6A CN115501234B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
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| CN202211173846.6A CN115501234B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202110880211.9A CN113616657B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparation of medicine for treating and/or preventing demyelinating diseases |
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| CN202211173846.6A Active CN115501234B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202110880211.9A Active CN113616657B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparation of medicine for treating and/or preventing demyelinating diseases |
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| JP6308699B2 (en) * | 2014-09-08 | 2018-04-11 | 国立大学法人大阪大学 | Preventive or therapeutic agent for demyelinating disease |
| WO2018022904A2 (en) * | 2016-07-27 | 2018-02-01 | Case Western Reserve University | Compounds and methods of promoting myelination |
| US20190175611A1 (en) * | 2016-08-12 | 2019-06-13 | The Regents Of The University Of California | Remyelination Therapy |
| WO2019126759A1 (en) * | 2017-12-22 | 2019-06-27 | Convelo Therapeutics, Inc. | Compounds and methods of promoting myelination |
| WO2019172969A1 (en) * | 2018-03-08 | 2019-09-12 | The Scripps Research Institute | Methods for promoting myelination and for treating demyelinating diseases |
| CN108379246A (en) * | 2018-05-16 | 2018-08-10 | 中国人民解放军第二军医大学 | Shikimic acid is preparing the application in preventing or treating demyelinating disease drug |
| US20210353642A1 (en) * | 2018-10-02 | 2021-11-18 | Case Western Reserve University | Compounds for treating myelin related disorders |
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| CN115501227B (en) | 2023-09-19 |
| CN115501227A (en) | 2022-12-23 |
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| CN115501233B (en) | 2023-11-07 |
| CN113616657A (en) | 2021-11-09 |
| CN115501233A (en) | 2022-12-23 |
| CN113616657B (en) | 2022-12-20 |
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