CN113616657B - Application of compound in preparation of medicine for treating and/or preventing demyelinating diseases - Google Patents
Application of compound in preparation of medicine for treating and/or preventing demyelinating diseases Download PDFInfo
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Abstract
The invention provides application of a compound in preparing a medicament for treating and/or preventing demyelinating diseases. 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.
Description
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 medicine for treating and/or preventing 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 is mainly lipid, accounting for about 70% of dry weight, and can protect axon, realize nerve impulse jump conduction, and accelerate nerve signal conduction speed. Oligodendrocyte precursor cells are stored in the brain of an adult, but are difficult to autonomously differentiate into oligodendrocytes and generate myelin sheaths 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 has been made to solve at least one of the above-mentioned problems occurring in the prior art. 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) propionamide (3- (3, 5-dimethyl-1H-pyrazo-1-yl) -N- ({ 1-oxo-2- [ (pyridin-3-yl) methyl ] -1H,2H,3H,4H-pyrro [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- (methoxamethyl) -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- (hydroxymethy) oxolan-2-yl ] -9H-purin-8-yl } hydrazin-1-ylidine) -1, 3-diazina-2, 4, 6-trione); the CAS number for formula IV is: 714914-49-5 with 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 (collapsed Fluid Meiosis-activating Sterol) in a hypercholesterolemia metabolic pathway by inhibiting TM7SF2, the cumulus cells secrete meiotic Sterol, and the CAS number is 64284-64-6), 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 formulae I to V in the agent for the treatment and/or prevention of a 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 beneficial effects of the invention are as follows: 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.
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 immunofluorescence results of compounds of formulae I-V of the present invention and DMSO negative controls on oligodendrocyte 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-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 the experiments: primary cultured Oligodendrocyte Precursor Cells (OPCs).
Experimental drugs and antibodies:
the medicine of the invention: compounds of formula I-V
Negative control drugs: DMSO (dimethylsulfoxide)
Positive control drug: thyroxine 3 (T) 3 )
Cell culture: killing an E14.5 ICR pregnant mouse by removing the neck, wiping the abdomen with an alcohol cotton ball, splitting, separating the uterus, sequentially performing immersion cleaning by 75% alcohol and PBS, transferring to a 60mm dish containing a proper amount of HBSS, and transferring to a biological safety cabinet for operation; under a dissecting microscope, fetal rats were isolated from the uterus using forceps and surgical scissors. Forceps tear the cerebral skin/skull, remove the olfactory bulb, cerebellum and basal ganglia, and transfer the remaining cerebral cortex to a new 60mm dish containing NPC medium. Forceps cut the head, limbs, tail and internal organs, 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) gently blowing and beating the small blocks by a pipetting gun, filtering the small blocks by a filter screen of 40 mu m, centrifuging the small blocks for 5min at 1000rpm, discarding the supernatant, adding a proper amount of NPC culture medium to resuspend the small blocks, transferring the small blocks to a 100mm dish to perform suspension culture (averagely culturing 3 cells extracted from fetal mice in each dish), counting the number of P0 generation, and culturing the small blocks for 2 to 3 days or subculturing when the diameter of a neurosphere reaches 100 mu m.
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 into a 96-well plate (pre-poly ornithine and Laminin coating), and culturing the cells/well in an OPC culture medium for 2 days to induce and differentiate NPC into OPC; 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); imaging the staining result by a high content imaging system Scan-R, taking the percentage of MBP + cells as an index, selecting a DMSO negative control group as a standard, and enabling the proportion of the MBP + cells to be higher than the standardIt can promote OPC differentiation.
Protein extraction and immunoblot analysis:
digesting the P5 generation neurosphere into single cells by Accutase enzyme according to the proportion of 1.2 multiplied by 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/well RAPI lysate, and standing at 4 deg.C for 30min; the supernatant was collected by scraping, centrifuged at 14000rpm at 4 ℃ for 15min, and the protein concentration was determined using the BCA kit. Adding instant protein loading 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. Pouring into a glass plate, adding deionized water, sealing, standing at room temperature for 30min, and solidifying; the deionized water was discarded, the concentrated gel (TEMED added) was added, followed by insertion of a comb to ensure no bubbles were formed, 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 each sample group 1 was added and the other samples in the same group were ratioed according to the absorbance value determined by the BCA kit. The strip was electrophoresed to the boundary between the separation gel and the concentration gel at a constant voltage of 120V for 20 min. Then 100V electrophoresis is carried out for 40min-60min until the Marker is fully developed. The PVDF membrane with proper size is cut off 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 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 percent of skimmed milk powder), and shaking and incubating at room temperature for 2 hours; absorbing the secondary antibody, washing for 3 times by TBST, 10min each time; 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, ". Indicates P<0.001, ". Indicates P<0.0001 when P<0.01, significant difference between groups as compared with the negative control group of 0.2% DMSO group. As can be seen, the MBP (oligodendrocyte maturation-expressing protein) positive cell rates (MBP) of formulas I-V + %) and 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 gave the best MBP-positive cell rate, i.e., the best oligodendrocyte precursor cell differentiation-promoting activity, 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 I for the preparation of a medicament for the treatment and/or prevention of demyelinating diseases:
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 the 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 demyelinating diseases is a compound of the formula I as the only active ingredient or a pharmaceutical composition containing the compound of the formula I.
5. Use according to claim 1, characterized in that: the content of the compound shown in the formula I 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 I 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 a compound of formula I as defined in claim 1 and pharmaceutically acceptable excipients.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110880211.9A CN113616657B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparation of medicine for treating and/or preventing demyelinating diseases |
| CN202211173609.XA CN115501233B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for treating and/or preventing demyelinating diseases |
| CN202211174824.1A CN115501235B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparation of medicine for preventing and treating demyelinating diseases |
| CN202211173846.6A CN115501234B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202211173737.4A CN115501227B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
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| 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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| CN202211173737.4A Division CN115501227B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202211174824.1A Division CN115501235B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparation of medicine for preventing and treating demyelinating diseases |
| CN202211173846.6A Division CN115501234B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202211173609.XA Division CN115501233B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for treating and/or preventing demyelinating diseases |
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| CN113616657A CN113616657A (en) | 2021-11-09 |
| CN113616657B true CN113616657B (en) | 2022-12-20 |
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| CN202211173737.4A Active CN115501227B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for preventing and treating demyelinating diseases |
| CN202211173609.XA Active CN115501233B (en) | 2021-08-02 | 2021-08-02 | Application of compound in preparing medicine for treating and/or preventing 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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| AU2001267882A1 (en) * | 2000-06-30 | 2002-01-14 | Chugai Seiyaku Kabushiki Kaisha | Preventives and remedies for diseases in association with demyelination |
| WO2004037159A2 (en) * | 2002-10-23 | 2004-05-06 | Obetherapy Biotechnology | Compounds, compositions and methods for modulating fat metabolism |
| US9551036B2 (en) * | 2013-02-25 | 2017-01-24 | Whitehead Institute For Biomedical Research | Metabolic gene mesenchymal signatures and uses thereof |
| WO2016039339A1 (en) * | 2014-09-08 | 2016-03-17 | 国立大学法人大阪大学 | Agent for preventing or treating demyelinating disease |
| EP3490556A4 (en) * | 2016-07-27 | 2020-04-15 | Case Western Reserve University | Compounds and methods of promoting myelination |
| EP3496725B1 (en) * | 2016-08-12 | 2022-10-05 | The Regents of The University of California | Remyelination therapies |
| WO2019126759A1 (en) * | 2017-12-22 | 2019-06-27 | Convelo Therapeutics, Inc. | Compounds and methods of promoting myelination |
| CA3093361A1 (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 |
| US12048678B2 (en) * | 2018-10-02 | 2024-07-30 | Case Western Reserve University | Compounds for treating myelin related disorders |
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