CN115501234A - Application of compound in preparing medicament for preventing and treating demyelinating disease - Google Patents
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Abstract
The invention provides application of a compound in preparing a medicament for preventing and treating demyelinating diseases. The compounds shown in the formulas I to V can promote the differentiation of oligodendrocyte precursor cells into oligodendrocyte and the myelination by inhibiting the accumulation of FF-MAS in a cholesterol metabolic pathway of TM7SF 2; promoting differentiation of original oligodendrocyte precursor cells to oligodendrocyte in brain of patients with demyelination disease, forming myelin sheath to wrap axon again, recovering nerve function decline caused by demyelination loss, and treating and/or relieving and/or preventing demyelination disease.
Description
The application is a divisional application with the application number of 202110880211.9, application date of 2021, 08 and 02, the title of the invention "application of compound in preparing medicine 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 preparing a medicament for preventing and treating demyelinating diseases.
Background
In the Central Nervous System (CNS) of vertebrates, myelination of axons enables a jump-type conduction of nerve impulses, increasing the speed of conduction of nerve impulses. Oligodendrocytes (OL) and Schwann cells (Schwann cell) produce myelin sheaths of the central and Peripheral Nervous Systems (PNS), respectively. Wherein, OL is generated by differentiation of Oligodendrocyte Precursor Cells (OPC). Multiple Sclerosis (MS), guillain-Barre syndrome (Guillain-Barre syndrome), neuromyelitis optica (NMO), and other demyelinating diseases can cause damage to and loss of myelin sheath of nerve axons, thereby causing neurological impairment. Normally, stored OPCs in the adult brain can be recruited to migrate to focal areas and differentiate into OLs, thereby generating myelin-enclosed axons. However, in pathological conditions, this process is hampered. Current therapies targeting the immune system can reduce immune-mediated damage in demyelinating diseases, but do not promote remyelination and axonal repair.
Myelin sheath contains lipid as main component, accounting for about 70% of dry weight, and can protect axon, realize nerve impulse jump conduction, and accelerate nerve signal conduction. Oligodendrocyte precursor cells are stored in the brain of an adult, but are difficult to autonomously differentiate into oligodendrocytes and generate myelin under the pathological condition of demyelinating diseases. Therefore, there is a need to find new compounds that promote differentiation of oligodendrocyte precursor cells.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the first aspect of the invention provides the application of the compound or the derivative thereof in preparing a medicament for treating and/or preventing the demyelinating disease, which can effectively treat and/or prevent the demyelinating disease.
In a second aspect of the invention, a pharmaceutical composition for the treatment and/or prevention of a demyelinating disease is provided.
According to a first aspect of the present invention, there is provided the use of a compound of formulae I to V below, or a derivative thereof, for the manufacture of a medicament for the treatment and/or prevention of a demyelinating disease:
wherein, the CAS number of the compound of the 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-pyrrolo [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-pyro [1,2-a ] pyrazin-3-yl } methyl) propenamide); the CAS number for the compound of formula II is 1775503-94-0, with the 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- (methoxymethyl) -1,2, 4-oxadiazin-5-yl ] -N-methylpyrrolidine-3-carboxamide); the CAS number of the compound of the formula III is 686301-37-1, and the chemical name is: 5- (2- {6-amino-9- [ (2S, 3S,4R, 5S) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl ] -9H-purin-8-yl } hydrazino-1-ylidone) -1, 3-diazine-2, 4,6-trione (5- (2- {6-amino-9- [ (2S, 3S,4R, 5S) -3,4-dihydroxy-5- (hydroxymethyl) oxolan-2-yl ] -9H-purin-8-yl } hydrozin-1-ylidine) -1, 3-diazina-2, 4, 6-trione); the CAS number for formula IV is: 714914-49-5, chemical name: 1,1'- (1, 2-phenylenebis (methylene)) bis (5-methylpyrimidine-2, 4 (1H, 3H) -dione) (1, 1' - (1, 2-phenylenebis (methyl)) bis (5-methylpyrimidine-2, 4 (1H, 3H) -dione)); the CAS number of the compound of formula V is 931589-90-1, the chemical name is: 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-tetrahydro-7- [2- (4-methoxyphenyl) ethyl ] -1,3-dimethyl-2,6-dioxo-1H-purin-8-yl ] thio ] -butanoic acid).
In the invention, the compounds shown in the formulas I to V can improve the accumulation of FF-MAS (falling Fluid Meiosis-activating Sterol, the secretion of Meiosis Sterol by cumulus cells with CAS number of 64284-64-6) in a hypercholesterolemia metabolic pathway through inhibiting TM7SF2, and the accumulation of FF-MAS can promote the differentiation of oligodendrocyte precursor cells into oligodendrocytes and myelination.
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 salt includes, but is not limited to, at least one of an inorganic acid salt, an organic acid salt, an alkyl sulfonate salt, and an aryl sulfonate salt; preferably, the inorganic acid salt includes, but is 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 sulfonate includes, but is not limited to, at least one of methyl sulfonate and ethyl sulfonate; the aryl sulfonate includes, but is not limited to, at least one of benzene sulfonate and p-toluene sulfonate.
In some more preferred embodiments of the invention, the agent for treating and/or preventing a demyelinating disease is an agent that promotes remyelination.
In some more preferred embodiments of the invention, the agent that promotes remyelination is an agent that promotes differentiation and maturation of oligodendrocyte precursor cells or promotes expression of myelin-associated protein.
In some more preferred embodiments of the present invention, the agent for treating and/or preventing a demyelinating disease is any one of the compounds of formulae I to V as the only active ingredient or a pharmaceutical composition comprising at least one of the compounds of formulae I to V.
In some more preferred embodiments of the present invention, the amount of any one of the compounds of formula I to formula V in the agent for treating and/or preventing demyelinating disease is 0.1 to 99wt%; preferably 1 to 90wt%; more preferably 10 to 85wt%.
In some more preferred embodiments of the present invention, the agent for treating and/or preventing demyelinating diseases is a decoction, powder, pill, medicated wine, lozenge, gum, plaster, medicated tea, starter, cake, lotion, stick, thread, strip, nail, moxibustion, ointment, pellet, microcapsule, intravenous emulsion, liposome preparation, aerosol, prodrug preparation, injection, mixture, oral ampoule, tablet, capsule, drop pill, emulsion, ointment, rubber plaster, film, sponge, iontophoresis, transdermal absorbent.
According to the second aspect of the invention, the invention provides a pharmaceutical composition for treating and/or preventing demyelinating diseases, which consists of at least one compound of formula I to formula V or a derivative thereof and pharmaceutically acceptable auxiliary materials.
The invention has the beneficial effects that: the compounds shown in the formulas I to V can promote the differentiation of oligodendrocyte precursor cells to oligodendrocytes and myelination by inhibiting the accumulation of FF-MAS in a cholesterol metabolic pathway of TM7SF 2; promoting differentiation of original oligodendrocyte precursor cells to oligodendrocyte in brain of patients with demyelination disease, forming myelin sheath to wrap axon again, recovering nerve function decline caused by demyelination loss, and treating and/or relieving and/or preventing demyelination disease.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 shows the dose-effect relationship between the compounds of formula I to formula V of the present invention for promoting differentiation of oligodendrocyte precursor cells.
FIG. 2 shows the immunofluorescence results of the DMSO negative controls and compounds of formulas I-V of the present invention on oligodendrocyte precursor cell differentiation, with a scale of 100 μm.
FIG. 3 shows the results of Western blotting of differentiation of oligodendrocyte precursor cells by the compounds of formula I to formula V according to the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and other embodiments obtained by those skilled in the art without inventive efforts are within the protection scope of the present invention based on the embodiments of the present invention.
Examples
The promoting effect of the compounds of formula I to formula V on Oligodendrocyte Precursor Cell (OPC) differentiation
The experimental method comprises the following steps:
in order to confirm the effect of the compounds of formula I to formula V on OPC differentiation, it was verified that the compounds of formula I to formula V can promote OPC differentiation and maturation.
Cells for experiments: primary cultured Oligodendrocyte Precursor Cells (OPCs).
Experimental drugs and antibodies:
the medicine of the invention is: compounds of formula I to formula V
Negative control drugs: DMSO (dimethylsulfoxide)
Positive control drug: thyroxine 3 (T) 3 )
Cell culture: removing neck to kill E14.5 ICR pregnant mouse, wiping abdomen with alcohol cotton ball, dissecting, separating uterus, sequentially soaking with 75% alcohol and PBS, transferring into 60mm dish containing appropriate amount of HBSS, and transferring to biological safety cabinet; under a dissecting microscope, fetal mice were separated from the uterus with forceps and surgical scissors. Forceps torn the cerebral skin/skull, removed the olfactory bulb, cerebellum and basal ganglia, and transferred the remaining cerebral cortex to a new 60mm dish containing NPC medium. The heads, limbs, tails and internal organs were cut with forceps and the trunk was transferred to a 60mm dish containing additional cold PBS for MEF extraction; cutting all cerebral cortex into 1mm with surgical scissors 3 And (3) slightly blowing the small blocks by using a pipette, passing through a 40-micron filter screen, centrifuging at 1000rpm for 5min, discarding the supernatant, adding an appropriate amount of NPC culture medium for resuspension, transferring the suspended cells into a 100-mm dish for suspension culture (average cells extracted from 3 fetal mice cultured in each dish) counted as P0 generation, and culturing for 2-3 days or until the diameter of a neurosphere reaches 100 microns for passage.
OPC differentiation experiments: digesting the P5 generation neurosphere into single cells by Accutase enzyme according to the proportion of 4 multiplied by 10 4 Planting the cells/well density into a 96-well plate (pre-poly ornithine and Laminin coating), and inducing NPC to differentiate into OPC after 2 days of OPC culture medium culture; discarding the OPC culture medium, washing 1 time with DPBS, replacing with OL culture medium, adding 0.05 μ M, 0.1 μ M, 1 μ M, 20 μ M compounds of formula I-V, setting negative control (DMSO, 0.2%, V/V) and positive control (T3, 100 nM) for each 96-well plate, differentiating OPC into OL for 3 days; the differentiated cells were fixed with 4% pfa and immunofluorescent-stained with MBP (myelin basic protein, MBP); and imaging the staining result by using a high content imaging system Scan-R, taking the percentage of MBP + cells as an index, and selecting a DMSO negative control group as a standard, wherein the MBP + cell proportion higher than the standard can promote OPC differentiation.
Protein extraction and immunoblot analysis:
the P5 generation neurospheres were digested into single cells by Accutase enzyme at 1.2X 10 6 Cell/well density was plated in 6-well plates (previously coated with polyornithine and Laminin). Extracting proteins after two-day OPC differentiation and three-day OL differentiation according to the above differentiation method; the medium was discarded and the DPBS was washed 1 time. Adding 150 μ L/hole RAPI lysate, and standing at 4 deg.C for 30min; the supernatant was collected by scraping, centrifuged at 14000rpm for 15min at 4 ℃ and the protein concentration was determined using the BCA kit. Adding instant protein sample buffer (denatured, reduced, 5X), heating at 100 deg.C for 10min to denature protein, and storing at-20 deg.C or immediately using.
Preparing 12% separation gel, adding TEMED and shaking up. Pouring into a glass plate, adding deionized water, sealing, standing at room temperature for 30min, and solidifying; the deionized water was discarded, the concentrated gum (TEMED added) was added, and then a comb was inserted to ensure no bubbles were generated and left to solidify at room temperature for 20 min. And (3) washing the rubber plate, putting the rubber plate into an electrophoresis tank, adding sufficient electrophoresis liquid, pulling out a comb, and adding 10 mu L and 5 mu L of activator respectively. The protein sample is added in the middle. mu.L of sample 1 was added to each group, and the other samples in the same group were added in a ratio calculated based on the absorbance value measured by the BCA kit. The strip was electrophoresed at a constant voltage of 120V for 20min to the boundary between the separation gel and the concentration gel. Then 100V electrophoresis is carried out for 40min-60min until the Marker is fully developed. The PVDF membrane with proper size is cut and immersed in methanol for activation for 5min. Adding a proper amount of membrane transferring liquid to a tray, and immersing the filter paper and the sponge pad into the membrane transferring liquid; prying the rubber plate, and removing the concentrated rubber and the redundant separation rubber around the concentrated rubber. Placed on filter paper. Opening the clamp for transferring the membrane, placing the membrane on the black surface, the spongy cushion, the filter paper, the adhesive, the PVDF membrane, the filter paper, the spongy cushion and the white surface, and clamping the clamp; and (3) placing the clamp into the film transferring groove, wherein the black surface of the clamp corresponds to the black surface of the film transferring groove, and the white surface of the clamp corresponds to the red surface of the film transferring groove. Pouring a proper amount of film transfer liquid, and placing two small ice boxes to a film transfer groove. And then placed in ice. The film is rotated for 1.5h at 300 mA.
Taking out the PVDF membrane from the membrane transferring tank, adding a proper amount of 5% skimmed milk powder, shaking at room temperature, and sealing for 2h; discarding 5% skimmed milk powder, washing with TBST for 3 times, each for 10min; adding a proper amount of primary antibody, and incubating overnight at 4 ℃; absorbing primary antibody, 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; absorbing secondary antibody, washing for 3 times (10 min each time) by TBST; and (3) luminous development imaging: ECL enhanced chemiluminescence solution A and solution B are mixed in equal volume, and are uniformly dripped on a membrane, and an instrument is used for exposure imaging.
The results are shown in fig. 1 to 3, and in fig. 1, "+" indicates P<0.01, ". X" indicates P<0.001, ". Indicates P<0.0001 when P<At 0.01, there was a significant difference between groups as compared to the negative control group, 0.2% dmso group. As can be seen, the MBP (oligodendrocyte maturation-expressing protein) positive cell rates (MBP) of formulas I-V + %) and the compound concentration, wherein 0.05. Mu.M of formula I, 0.1. Mu.M of formula II, 0.1. Mu.M of formula III, 0.1. Mu.M of formula IV and 1. Mu.M of formula V had the best MBP-positive cell rate, i.e., the best oligodendrocyte precursor differentiation-promoting activity, as compared to the negative control group.
In FIG. 2, blue is indicated as nucleus (stained by DAPI), red is indicated as MBP, and the scale is 100 μm, and it can be seen that the MBP expression levels of formulas I to V were significantly increased as compared to the negative control group, which was 0.2% DMSO, directly demonstrating that formulas I to V can promote differentiation and maturation of oligodendrocyte precursor cells at the corresponding concentrations.
As can be seen from FIG. 3, the expression of MBP in formulas I to V was 0.2% higher than that in the negative control group by the DMSO group according to the amount of MBP protein expressed, i.e., formulas I to V promoted MBP expression, indicating that formulas I to V were able to promote differentiation and maturation of oligodendrocyte precursor cells.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (8)
1. Use of a compound of formula III or a derivative thereof for the manufacture of a medicament for the treatment and/or prevention of a demyelinating disease:
2. use according to claim 1, characterized in that: the medicament for treating and/or preventing the demyelinating disease is a medicament for promoting remyelination.
3. Use according to claim 2, characterized in that: the medicament for promoting remyelination is a medicament for promoting differentiation and maturation of oligodendrocyte precursor cells or promoting expression of myelin-associated proteins.
4. Use according to claim 1, characterized in that: the medicament for treating and/or preventing the demyelinating disease is the compound of the formula III as the only active ingredient or a pharmaceutical composition containing the compound of the formula III.
5. 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 0.1-99 wt%.
6. 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 1-90 wt%.
7. Use according to claim 1, characterized in that: the medicine for treating and/or preventing demyelinating disease is decoction, powder, pill, medicated wine, lozenge, gum, tea, yeast, cake, lotion, stick, thread, strip, nail, moxibustion, paste, pellet, liposome, aerosol, injection, mixture, tablet, capsule, dripping pill, emulsion, membrane, sponge, iontophoresis agent, and transdermal absorbent.
8. A pharmaceutical composition for the treatment and/or prevention of demyelinating diseases, characterized in that: consists of at least one compound of formula III or a derivative thereof according to claim 1 and pharmaceutically acceptable excipients.
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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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| 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 |
| CN115501234B (en) | 2023-08-08 |
| CN113616657A (en) | 2021-11-09 |
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| CN115501235B (en) | 2023-11-07 |
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