Application of SIRT7 inhibitor 97491 in preparation of medicine for treating autoimmune demyelination disease
The pharmaceutical composition prepared by using the SIRT7 inhibitor 97491 solves the problem of the lack of effective treatment for autoimmune demyelinating diseases in the prior art, and achieves both preventive and therapeutic effects on demyelinating diseases, with both safety and efficacy.
Patent Information
- Application Number
- CN202411237948.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-05
- Publication Date
- 2026-03-10
AI Technical Summary
There is a lack of effective drugs in the current technology for the prevention and treatment of autoimmune demyelinating diseases, especially demyelinating diseases such as multiple sclerosis. Moreover, existing drugs cannot repair damaged neurons and have toxic side effects with long-term use.
SIRT7 inhibitor 97491 and its pharmaceutically acceptable salts are used to prepare various dosage forms, such as solutions, lyophilized powder for injection, and pills, for intraperitoneal injection or other routes of administration to prevent, alleviate and treat autoimmune demyelinating diseases.
SIRT7 inhibitor 97491 can significantly improve demyelinating symptoms in animal models, reduce inflammatory cell infiltration, restore myelin, reduce pro-inflammatory factor expression, improve neurological function, and provide a safe and effective treatment option.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to application of SIRT7 inhibitor 97491 and / or a pharmaceutically acceptable salt thereof in preparation of a medicine for preventing, alleviating and / or treating an autoimmune demyelinating disease, and belongs to the technical field of medicines. BACKGROUND
[0002] Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the central nervous system (CNS) mediated by immunity. More than 2 million people worldwide are affected, which causes serious harm to human health and heavy economic burden to the society. The pathogenesis of multiple sclerosis is complex, the cause is unknown, and it cannot be cured at present, so patients need long-term treatment. Multiple sclerosis is mainly characterized by inflammation and demyelination in the brain, spinal cord and optic nerve, and its clinical manifestations are wide-ranging, including muscle weakness, sensory disturbance, cognitive dysfunction and fatigue. The cause of multiple sclerosis is not clear, and it may be related to multiple factors such as heredity, environment and infection. According to the clinical manifestations of patients, multiple sclerosis can be divided into four types: relapsing-remitting type, which is characterized by alternating relapse and remission without obvious progression; primary progressive type, which is characterized by continuous deterioration after onset; secondary progressive type, which is characterized by continuous deterioration after relapsing-remitting type; and progressive relapsing type, which is characterized by gradual progression after onset accompanied by relapse. At present, the drugs for clinical treatment are mainly for patients with relapsing-remitting type.
[0003] Multiple sclerosis is considered to be an autoimmune disease mainly caused by autoimmune immune cells entering the CNS through the blood-brain barrier. Its early lesions are characterized by peripheral immune cell infiltration and blood-brain barrier (BBB) leakage. The cell infiltration is mainly macrophages, followed by CD8 + T cells, CD4 + T cells, B cells and plasma cells are relatively less. The composition of T cells does not change with the development of the disease, but the relative proportion of B cells and plasma cells increases. Microglia and macrophages remain in a state of chronic activation throughout the disease process, forming patches of myelin and oligodendrocyte loss. With the progression of the disease, patients develop focal white matter lesions in the brain, and brain and spinal cord damage is not obvious, but brain atrophy is common, brain atrophy is accompanied by ventricular enlargement, and astrocytes form multiple sclerosis glial scars in white matter lesions. Demyelination also occurs in the cerebral cortex, nuclei and gray matter of the spinal cord, but the demyelinated areas of the white matter can be partially repaired by myelin regeneration; in addition, the disease process not only affects myelin, but also causes axonal and neuronal degeneration, resulting in irreversible disability in patients.
[0004] Over the past two decades, as the pathogenesis of multiple sclerosis is increasingly understood, researchers have developed a variety of drugs targeting the special physiological pathways of the disease. Currently, drugs for treating multiple sclerosis are mainly divided into five categories: immunomodulators, hormones, monoclonal antibodies, interferons, and nerve repair agents. These drugs can alleviate disease progression, control patients' symptoms, but are ineffective in repairing damaged neurons, have no improvement effect on patients' functional disability, and have serious toxic side effects with long-term use.
[0005] The experimental autoimmune encephalomyelitis (EAE) model is a classic animal model of multiple sclerosis, which is initiated by myelin-specific brain helper T cells, resulting in inflammatory infiltration of the central nervous system and demyelination. Its biochemical, immunological and pathological characteristics are very similar to multiple sclerosis. In addition, rat and mouse EAE can also be used as an ideal animal model for studying experimental autoimmune encephalomyelitis, opticospinal encephalomyelitis and acute disseminated encephalomyelitis, and other autoimmune demyelinating diseases. It is similar to human demyelinating diseases in terms of clinical, pathological, immunological and biochemical changes, and is widely used.
[0006] SIRT7 inhibitor 97491 (1,3-Benzenediamine, N1-[5-(4-chlorophenyl)-2-oxazolyl]-) is a specific SIRT7 inhibitor with high selectivity for SIRT7, and its molecular formula is C 15 H 12 ClN3O. Studies have shown that SIRT7 inhibitor 97491 reduces the deacetylase activity of SIRT7 in a dose-dependent manner, increases the stability of p53, and thus inhibits tumor growth in balb / c mice; SIRT7 inhibitor 97491 can also promote apoptosis by affecting the caspase pathway. In addition, literature research shows that SIRT7 inhibitors can reduce the inflammatory response of mouse colon. The above reports confirm that SIRT7 inhibitor 97491 has potential pharmacological activity.
[0007] So far, there is no patent related to the pharmacological effect of SIRT7 inhibitor 97491 (1,3-Benzenediamine, N1-[5-(4-chlorophenyl)-2-oxazolyl]-), and there is no research report on the treatment of autoimmune demyelinating diseases by SIRT7 inhibitor 97491. Therefore, the application of SIRT7 inhibitor 97491 in the preparation of drugs for preventing, alleviating and / or treating autoimmune demyelinating diseases is a new use of SIRT7 inhibitor 97491, which is a new discovery obtained through a large number of animal experiment research. The new invention mainly relates to the preparation of drugs and drug combinations, and the application in the preparation of drugs for preventing, alleviating and / or treating autoimmune demyelinating diseases. At present, there is no report on the direct or indirect effect of the compound on autoimmune demyelinating diseases at home and abroad. SUMMARY
[0008] The technical problem to be solved by the present application is to provide the application of SIRT7 inhibitor 97491 (1,3-Benzenediamine, N1-[5-(4-chlorophenyl)-2-oxazolyl]-) in the preparation of drugs for preventing, alleviating and / or treating autoimmune demyelinating diseases.
[0009] To solve the technical problems of the present application, the present application provides the following technical solutions:
[0010] The first aspect of the technical scheme of the present application is to provide the application of SIRT7 inhibitor 97491 (1,3-Benzenediamine, N1-[5-(4-chlorophenyl)-2-oxazolyl]-) and its pharmacologically acceptable salt as shown in formula (I) in the preparation of drugs for preventing, alleviating and / or treating autoimmune demyelinating diseases,
[0011]
[0012] The autoimmune demyelination diseases include but are not limited to demyelination autoimmune diseases of central nervous system (CNS) such as multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis, leukoencephalitis and transverse myelitis; demyelination autoimmune diseases affecting peripheral nervous system such as acute inflammatory demyelinating polyneuropathy (AIDP; Guillain-Barre syndrome), chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, Motor and Sensory Neuropathy (HMSN), Hereditary Sensorimotor Neuropathy (HSMN), Peroneal Muscular Atrophy, Charcot-Marie-Tooth Disease and the like.
[0013] The multiple sclerosis includes relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and progressive-relapsing multiple sclerosis.
[0014] A female C57BL / 6 mouse is used to establish an EAE model. The effect of SIRT7 inhibitor 97491 on the disease score of the animal is detected; the strength of the limbs of the animal is observed through a hanging experiment, and the treatment condition is observed. H&E staining and LFB staining are applied to detect the improvement effect of SIRT7 inhibitor 97491 on the inflammatory cell infiltration and demyelination in the spinal cord of the experimental animal. According to this, the role of SIRT7 inhibitor 97491 in preparing a drug for preventing, relieving and / or treating autoimmune demyelination diseases is determined.
[0015] The second aspect of the technical scheme of the present application is to provide an application of a pharmaceutical composition in preparing a drug for preventing, relieving and / or treating autoimmune demyelination diseases, characterized in that the pharmaceutical composition contains an effective dose of SIRT7 inhibitor 97491 as shown in formula (I) and a pharmaceutical excipient,
[0016]
[0017] The pharmaceutical composition, in addition to containing SIRT7 inhibitor 97491 as the active pharmaceutical ingredient, also contains other active ingredients. The pharmaceutical composition includes the following dosage forms: solution, suspension, lyophilized powder for injection, emulsion, pills, capsules, powder, controlled release, sustained release formulations, and microparticle delivery systems. The pharmaceutical excipients include starch, dextrin, sodium polymethyl cellulose, magnesium stearate, and talc. The product is selected from pharmaceuticals and health products.
[0018] The present invention therefore also relates to the use of pharmaceutical compositions using the SIRT7 inhibitor 97491 of the present invention as the active ingredient in the prevention, relief, and / or treatment of autoimmune demyelinating diseases. The pharmaceutical compositions can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be formulated by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.
[0019] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit doses via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc. The dosage form can be liquid, solid, or semi-solid. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc. The compounds of this invention can be formulated into conventional formulations, as well as sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.
[0020] For the preparation of tablets of the present application, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. For the preparation of capsules of the administration unit, the effective ingredient, the compound of the present application, can be mixed with diluents and glidants, and the mixture can be directly placed in hard or soft capsules. The effective ingredient, the compound of the present application, can also be mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed in hard or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for the preparation of tablets of the compound of the present application can also be used for the preparation of capsules of the compound of the present application. For the preparation of injections of the compound of the present application, water, ethanol, isopropyl alcohol, propylene glycol or their mixtures can be used as solvents, and appropriate amounts of solubilizers, co-solubilizers, pH adjustors and osmotic pressure adjustors commonly used in the art can be added. The solubilizers or co-solubilizers can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjustors can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjustors can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If lyophilized powder injections are prepared, mannitol, glucose, etc. can also be added as supporting agents. In addition, if necessary, coloring agents, preservatives, flavors, flavoring agents or other additives can also be added to the pharmaceutical preparations. To achieve the purpose of medication and enhance the therapeutic effect, the drugs or pharmaceutical compositions of the present application can be administered by any known administration method.
[0021] Beneficial technical effects
[0022] 1. The compound SIRT7 inhibitor 97491 of the present application can prevent, alleviate and / or treat autoimmune demyelinating diseases, and provides a new structural type of drug selection for the clinical treatment of autoimmune demyelinating diseases.
[0023] 2. The compound SIRT7 inhibitor 97491 of the present application can achieve therapeutic and preventive effects with small amount of intraperitoneal injection. The drug is safe and reliable. As a drug, it has obvious advantages. BRIEF DESCRIPTION OF DRAWINGS
[0024] Figure 1 Effect of SIRT7 inhibitor 97491 on disease score of EAE mice. In this experiment, the disease score of EAE model mice was significantly higher than that of the normal control group. After administration, the disease score of SIRT7 inhibitor 97491 administration group was significantly lower than that of the EAE model group.
[0025] Figure 2 Effect of SIRT7 inhibitor 97491 on the hanging time of EAE mice. In this experiment, compared with the normal control group, the hanging time of EAE model mice on the iron wire was significantly reduced, and SIRT7 inhibitor 97491 could prolong the hanging time of EAE mice. ###P<0.001 vs. normal control group, ***P<0.001 vs. EAE model group.
[0026] Figure 3 Effect of SIRT7 inhibitor 97491 on the hanging classification of EAE mice. ###P<0.001 vs. normal control group; ***P<0.001 vs. EAE model group.
[0027] Figure 4 Effect of SIRT7 inhibitor 97491 on inflammatory cell infiltration in the spinal cord of EAE mice. In this experiment, compared with the normal control group, the inflammatory cell infiltration in the spinal cord of EAE model mice was significantly inhibited, and SIRT7 inhibitor 97491 could significantly inhibit the inflammatory cell infiltration in the spinal cord of EAE mice.
[0028] Figure 5 Effect of SIRT7 inhibitor 97491 on demyelination in the spinal cord of EAE mice. In this experiment, after LFB (Luxol Fast Blue) staining, compared with the normal control group, the spinal cord of EAE model mice showed demyelination lesions with a larger area. SIRT7 inhibitor 97491 could reduce the white area of EAE mice spinal cord and effectively improve the demyelination of EAE mice spinal cord.
[0029] Figure 6Effect of SIRT7 inhibitor 97491 on mRNA levels of proinflammatory factors in the spinal cord of EAE mice. In this experiment, the mRNA levels of proinflammatory factors TNF-α, IL-6, IL-1β and MCP-1 in the spinal cord of EAE model mice were significantly increased compared with the normal control group, while 97491 could significantly inhibit the mRNA levels of proinflammatory factors TNF-α, IL-6, IL-1β and MCP-1 in the spinal cord of EAE mice.##P<0.01, ###P<0.001 vs. normal control group; *P<0.05, **P<0.01, ***P<0.001 vs. EAE model group.
[0030] Figure 7 Effect of SIRT7 inhibitor 97491 on M1 / M2 type microglial cell polarization in the spinal cord of EAE mice. In this experiment, 97491 could inhibit the expression of M1 type microglial cell marker CD16, CD32, CD68 and CD86 mRNA levels in the spinal cord of EAE mice, thereby inhibiting the polarization of M1 type microglial cells in the spinal cord of EAE mice; and 97491 could increase the expression of M2 type microglial cell marker CD206 mRNA levels, promote the conversion of microglial cells to M2 type, and play an anti-inflammatory role.###P<0.001 vs. normal control group; *P<0.05, **P<0.01, ***P<0.001 vs. EAE model group. DETAILED DESCRIPTION
[0031] The pharmacological effects of SIRT7 inhibitor 97491 in preventing, alleviating and / or treating autoimmune demyelinating diseases are further illustrated below.
[0032] The following examples illustrate the present application in more detail, but are not intended to limit the present application in any way.
[0033] Example 1: Improvement effect of SIRT7 inhibitor 97491 on behavior of EAE mice
[0034] 1.1 Establishment of experimental autoimmune encephalomyelitis mouse model and administration
[0035] Experimental principle
[0036] C57BL / 6 mice were induced with MOG 35-55 to establish an EAE model.
[0037] Experimental method
[0038] Female C57BL / 6J mice, 6 weeks old, weighing 16-18 g, after adaptive feeding for 3-5 days, subcutaneous injection of MOG35-55300 μg and intravenous injection of 400 ng of pertussis toxin to establish an experimental autoimmune encephalomyelitis animal model (EAE). At the same time, a normal control group was set up. The animals began to develop symptoms 11 days after modeling, and different degrees of limb paralysis occurred, confirming the success of the mouse experimental autoimmune encephalomyelitis model.
[0039] After immunization, female C57BL / 6 mice were randomly divided into 2 groups, including EAE control group and 3 mg / kg SIRT7 inhibitor 97491 administration group. After grouping, intraperitoneal injection was performed once a day, and continuous administration was performed until the 28th day of modeling. The normal control group and the EAE model group were given the same volume of solvent control (2% DMSO + 40% PEG300 + 5% Tween-80 + 53% normal saline). Since the onset of the disease, the disease score was measured every day, and the animal death was recorded. The suspension classification of the animals was measured on the 7th day, 14th day, 21st day and 28th day after immunization, and the suspension time of the animals on the iron wire was measured on the 28th day.
[0040] Experimental results
[0041] The animals began to develop symptoms on the 11th day after immunization, and weight loss and reduced neurological function scores occurred.
[0042] 1.2 Effect of SIRT7 inhibitor 97491 on disease score of EAE mice
[0043] Experimental method
[0044] The experimental mice were scored for disease every day after modeling, and the scoring criteria were as follows: 0 points: normal mice; 0.5 points: tail weakness; 1 point: complete tail paralysis; 1.5 points: one hind limb weakness; 2 points: both hind limbs weakness; 2.5 points: one hind limb paralysis, the other hind limb weakness; 3 points: both hind limbs paralysis; 3.5 points: partial forelimb weakness; 4 points: partial forelimb paralysis; 4.5 points: complete forelimb paralysis; 5 points: death.
[0045] Experimental results
[0046] In this experiment, the disease score of the EAE model group mice after the onset of the disease was significantly higher than that of the normal control group. After administration, the overall disease symptoms of the SIRT7 inhibitor 97491 administration group mice were reduced, and the disease score was significantly lower than that of the EAE model group, confirming that the SIRT7 inhibitor 97491 had a significant improvement effect on the neurological function of EAE mice. The results are shown in Figure 1 .
[0047] 1.3 Effect of SIRT7 inhibitor 97491 on suspension time of EAE mice
[0048] Experimental method
[0049] On day 28 after modeling, the falling time of mice from the 180° iron wire net was measured, and the time > 120 s was calculated as 120 s.
[0050] Experimental results
[0051] In this experiment, compared with the normal control group, the suspension time of EAE model mice on the iron wire net was significantly reduced, and SIRT7 inhibitor 97491 could prolong the suspension time of EAE mice, which confirmed that SIRT7 inhibitor 97491 had a significant improvement effect on the motor function of EAE mice. The results are shown in Figure 2 and Table 1.
[0052] Table 1 Effect of SIRT7 inhibitor 97491 on the suspension time of MOG-induced EAE mice
[0053]
[0054] Mean ± SEM (n = 10).
[0055] ### P < 0.001 vs. normal control group, *** P < 0.001 vs. EAE model group.
[0056] 1.4 Effect of SIRT7 inhibitor 97491 on the suspension rating of EAE mice
[0057] Experimental method
[0058] On day 7, 14, 21 and 28 after modeling, the forepaws of mice were suspended on a balance rope 30 cm from the ground, and the limb suspension state of mice on the balance rope was observed and scored, and the rating criteria were as follows: 5 points: hold the rope and can pull with hind limbs, tail around the rope; 4 points: hold the rope and can pull with hind limbs, tail raised but cannot wrap the rope; 3 points: hold the rope and can pull with hind limbs, tail drooping; 2 points: raise the hind limbs, hold the rope but cannot pull; 1 point: raise the hind limbs, but cannot hold the rope; 0 point: unable to raise the hind limbs.
[0059] Experimental results
[0060] In this experiment, compared with the normal control group, the suspension score of EAE model mice after onset was significantly reduced, and after administration, compared with the EAE model group, the suspension score of EAE mice in the SIRT7 inhibitor 97491 administration group was significantly increased in a time-dependent manner. The results are shown in Figure 3 and Table 2.
[0061] Table 2 Effect of SIRT7 inhibitor 97491 on the suspension rating of MOG-induced EAE mice
[0062]
[0063] Mean ± SEM (n = 10).
[0064] ***P<0.001 vs. normal control group; ***P<0.001 vs. EAE model group.
[0065] Example 2: Effect of SIRT7 inhibitor 97491 on inflammatory cell infiltration and demyelination in spinal cord of EAE model mice
[0066] 2.1 Establishment of EAE mouse model and administration
[0067] The experimental principle, experimental method and experimental results are the same as those in Example 1.1.
[0068] 2.2 Effect of SIRT7 inhibitor 97491 on inflammatory cell infiltration in spinal cord of EAE mice
[0069] Experimental method
[0070] On day 28 after modeling, 6 mice in each group were anesthetized with 4% tri- bromoethanol. First, physiological saline was used for perfusion, and then 4% paraformaldehyde was used for perfusion until the animal limbs were hard. The spinal cord was taken out and fixed in 4% paraformaldehyde. The spinal cord was made into paraffin sections, and hematoxylin-eosin (H&E) staining was performed to observe the inflammatory cell infiltration in the spinal cord of EAE mice.
[0071] Experimental results
[0072] In this experiment, compared with the normal control group, the inflammatory cell infiltration in the spinal cord of EAE model mice was significantly inhibited by 3 mg / kg SIRT7 inhibitor 97491, which confirmed that SIRT7 inhibitor 97491 could improve the inflammatory cell infiltration in the spinal cord of EAE mice. The results are shown in Figure 4 .
[0073] 2.3 Effect of SIRT7 inhibitor 97491 on demyelination in spinal cord of EAE mice
[0074] Experimental method
[0075] On day 28 after modeling, 6 mice in each group were anesthetized with 4% tri- bromoethanol. First, physiological saline was used for perfusion, and then 4% paraformaldehyde was used for perfusion until the animal limbs were hard. The spinal cord was taken out and fixed in 4% paraformaldehyde. The spinal cord was made into paraffin sections, and hematoxylin-eosin (H&E) staining was performed to observe the inflammatory cell infiltration in the spinal cord of EAE mice.
[0076] Experimental results
[0077] In this experiment, after LFB staining, compared with the normal control group, the spinal cord of EAE model mice showed demyelinating lesions with a larger area. The SIRT7 inhibitor 97491 could reduce the area of white matter in the spinal cord of EAE mice, effectively improving the demyelination. Results are shown below. Figure 5 .
[0078] Example 3: Effects of SIRT7 inhibitor 97491 on pro-inflammatory factors in the spinal cord of EAE mice and its regulation of polarization state of M1 / M2 microglia.
[0079] 3.1 Establishment of the EAE mouse model and drug administration
[0080] The experimental principle, experimental method, and experimental results are the same as in Example 1.1.
[0081] 3.2 Effects of SIRT7 inhibitor 97491 on the mRNA levels of pro-inflammatory factors in the spinal cord of EAE mice
[0082] Experimental methods
[0083] On day 28 after modeling, six mice from each group were anesthetized with 4% tribromoethanol. After cervical dislocation and decapitation, the spinal cord was harvested and RNA was extracted. The RNA was reverse transcribed into cDNA, and the mRNA levels of pro-inflammatory factors TNF-α, IL-6, IL-1β, and MCP-1 were detected using qRT-PCR.
[0084] Experimental results
[0085] In this experiment, compared with the normal control group, the mRNA levels of pro-inflammatory factors TNF-α, IL-6, IL-1β, and MCP-1 in the spinal cord of EAE model mice were significantly increased, while the SIRT7 inhibitor 97491 significantly inhibited the mRNA levels of these factors in EAE mice. Results are shown below. Figure 6 .
[0086] 3.3 Experimental Methods for the Regulation of Polarization State of M1 / M2 Microglia in the Spinal Cord of EAE Mice by SIRT7 Inhibitor 97491
[0087] On day 28 after modeling, six mice from each group were anesthetized with 4% tribromoethanol. After cervical dislocation and decapitation, the spinal cord was harvested and RNA was extracted. The RNA was reverse transcribed into cDNA, and the mRNA levels of M1 microglia markers CD16, CD32, CD68, and CD86, as well as the M2 microglia marker CD206, were detected using qRT-PCR.
[0088] Experimental results
[0089] In this experiment, the SIRT7 inhibitor 97491 inhibited the expression of CD16, CD32, CD68, and CD86 mRNA markers of spinal cord M1 microglia in EAE mice, thereby suppressing spinal cord M1 microglia polarization in EAE mice. In the EAE model group, the level of CD206 mRNA, a marker of spinal cord M2 microglia, was significantly decreased, while the SIRT7 inhibitor 97491 effectively increased CD206 mRNA expression, promoting microglia transformation to M2 type. Results are shown below. Figure 7 .
Claims
1. Use of SIRT7 inhibitor 97491 as shown in formula (I) and / or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, alleviating and / or treating an autoimmune demyelinating disease.
2. Use according to claim 1, characterized in that, The autoimmune demyelinating disease includes demyelinating autoimmune diseases of the central nervous system and demyelinating autoimmune diseases affecting the peripheral nervous system.
3. Use according to claim 2, characterised in that, The demyelinating autoimmune diseases of the central nervous system include multiple sclerosis, neuromyelitis optica spectrum disorders, acute disseminated encephalomyelitis, leukoencephalitis and transverse myelitis. The demyelinating autoimmune diseases affecting the peripheral nervous system include acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, anti-MAG peripheral neuropathy, motor and sensory neuropathy, hereditary sensory motor neuropathy, Charcot-Marie-Tooth disease, progressive neural Charcot-Marie-Tooth disease.
4. Use according to claim 3, characterised in that, The multiple sclerosis includes relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis and progressive-relapsing multiple sclerosis.
5. Use of a pharmaceutical composition in the manufacture of a medicament for preventing, alleviating and / or treating an autoimmune demyelinating disease, characterized in that, The pharmaceutical composition contains an effective dose of SIRT7 inhibitor 97491 as shown in formula (I), and optionally a pharmaceutically acceptable pharmaceutical excipient, 6. Use according to claim 5, characterised in that, The pharmaceutical composition contains SIRT7 inhibitor 97491 as a pharmaceutical active ingredient in addition to other active ingredients.
7. Use according to any one of claims 5-6, characterized in that, The pharmaceutical composition includes the following dosage forms: solution, suspension, lyophilized powder, emulsion, pill, capsule, powder, controlled release, sustained release preparation and microsomal drug delivery system.
8. Use according to claim 5, characterised in that, The pharmaceutical excipients include starch, dextrin, sodium polymethylcellulose, magnesium stearate, talc.