Application of IDH1 inhibitor in preparation of medicine for treating central nervous system demyelination disease

Abstract

The invention discloses application of an IDH1 inhibitor in preparation of a medicine for treating a central nervous system demyelination disease. Research finds that the IDH1 inhibitor can significantly improve the body weight and neurological function clinical score of a model mouse and alleviate demyelination. Therefore, the IDH1 inhibitor disclosed by the invention can be used for treating the central nervous system demyelination disease and has an important clinical application value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and particularly relates to the use of an IDH1 inhibitor in the preparation of a medicament for treating demyelinating diseases of the central nervous system. Background Art

[0002] Demyelinating diseases of the central nervous system (CNS) are a class of autoimmune diseases characterized by demyelination of the central nervous system (CNS), including multiple sclerosis and neuromyelitis optica spectrum disorders. Their pathogenesis involves abnormal activation of immune cells, leading to demyelination, neuronal damage, and neurological dysfunction. Currently, treatments for demyelinating diseases of the CNS primarily include immunomodulators and anti-inflammatory drugs. However, existing therapies still suffer from limited efficacy, significant side effects, and the development of drug resistance, necessitating the development of new treatment strategies. Summary of the Invention

[0003] Currently, the treatment of demyelinating diseases of the central nervous system (CNS) remains challenging, particularly due to the limited regulatory approaches for CNS immune cells. To address these technical challenges, the present invention provides the use of isocitrate dehydrogenase 1 (IDH1) inhibitors in the preparation of medicaments for treating CNS demyelinating diseases. Specifically, the present invention encompasses the following.

[0004] The first aspect of the present invention provides use of an IDH1 inhibitor in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system.

[0005] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the IDH1 inhibitor comprises a compound represented by Formula I:

[0006]

[0007] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the improvement or treatment of a demyelinating disease of the central nervous system includes at least one of the following situations:

[0008] (1) Inhibit myelin destruction or improve demyelination;

[0009] (2) Improve or enhance neurological function;

[0010] (3) Improve motor dysfunction;

[0011] (4) Slow down weight loss.

[0012] In certain embodiments, the IDH1 inhibitor according to the present invention is used in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the demyelinating disease of the central nervous system includes multiple sclerosis, autoimmune encephalomyelitis or neuromyelitis optica spectrum disorder.

[0013] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the medicament further comprises a pharmaceutically acceptable carrier.

[0014] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the pharmaceutically acceptable carrier comprises at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative and an antioxidant.

[0015] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a drug for improving or treating a demyelinating disease of the central nervous system, wherein the improvement or treatment is achieved by administering a therapeutically effective amount of the drug to a subject in need thereof.

[0016] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the subject comprises a mammal.

[0017] In certain embodiments, the use of the IDH1 inhibitor according to the present invention in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, wherein the therapeutically effective amount is 0.01-1000 mg / Kg.

[0018] The second aspect of the present invention provides the use of an IDH1 inhibitor in the preparation of a drug for treating demyelinating diseases of the central nervous system in combination with other drugs.

[0019] The present invention has found that IDH1 inhibitors can significantly improve body weight and neurological function clinical scores in mouse models and reduce demyelination. Therefore, the IDH1 inhibitors of the present invention can be used to treat demyelinating diseases of the central nervous system and have important clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The construction process and drug administration method of EAE mice are shown.

[0021] Figure 2 It was shown that HY12475 could improve the clinical scores of neurological function in EAE mice.

[0022] Figure 3 It was shown that HY12475 can inhibit body weight loss in EAE.

[0023] Figure 4 It was shown that HY12475 can improve demyelination in EAE mice. DETAILED DESCRIPTION

[0024] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0025] It should be understood that the terms described in the present invention are only for describing particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges in the present invention, it should be understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Each smaller range between any stated value or intermediate value within a stated range and any other stated value or intermediate value within the stated range is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0026] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of any conflict with any incorporated document, the content of this specification shall prevail.

[0027] application

[0028] In one aspect of the present invention, an IDH1 inhibitor is provided for use in the preparation of a drug for improving or treating a demyelinating disease of the central nervous system. In a preferred embodiment, the IDH1 inhibitor is HY12475 (CAS No. 1355326-21-4, C 30 H 31 FN4O2, molecular weight 498.59), which has the structural formula shown in Formula I:

[0029]

[0030] In the present invention, the central nervous system demyelinating disease is not particularly limited, and examples thereof include but are not limited to multiple sclerosis, autoimmune encephalomyelitis, neuromyelitis optica spectrum disorder, etc. In a specific embodiment, the central nervous system demyelinating disease is multiple sclerosis.

[0031] In the present invention, the term "treat or improve" refers to therapeutic treatment or preventive measures, the purpose of which is to prevent or slow down (reduce) the physiological changes or disturbances that are not expected to occur, such as the progression of a demyelinating disease of the central nervous system. Useful or desired clinical outcomes include, but are not limited to, the following detectable or undetectable results, including alleviation of symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete). Those in need of treatment include those who have already suffered from a demyelinating disease of the central nervous system or those who need to treat or improve a demyelinating disease of the central nervous system. In certain embodiments, the therapeutic or improving effect is selected from at least one of the following: (1) inhibiting myelin destruction or improving demyelination caused by multiple sclerosis; (2) improving or enhancing neurological function damage and disorders caused by multiple sclerosis, such as neuronal damage and neurological dysfunction; (3) improving motor dysfunction caused by multiple sclerosis; (4) slowing down weight loss caused by multiple sclerosis; (5) inhibiting the activation of macrophage inflammasomes and the production of inflammatory factors, and the production of microglial inflammatory factor IL-1β caused by multiple sclerosis.

[0032] In the present invention, the medicament comprising the IDH1 inhibitor may further comprise a pharmaceutically acceptable carrier. In the present invention, a pharmaceutically acceptable carrier is involved in carrying or delivering the agent from one organ or part of the body to another organ or part of the body. Each carrier is "acceptable" if it is compatible with the other ingredients of the formulation (e.g., the compound of Formula I) and does not harm the patient.

[0033] In the present invention, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or medium, which includes at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative and an antioxidant. Examples of diluents include, but are not limited to, physiological saline, aqueous buffer solutions, solvents, dispersion vehicles, etc.; fillers include, but are not limited to, starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include, but are not limited to, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include, but are not limited to, water, ethanol, etc.; binders include, but are not limited to, hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc.; disintegrants include, but are not limited to, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include, but are not limited to, magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica gel, talc, etc.; sweeteners include, but are not limited to, sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, aspartame, etc.; preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, etc.; antioxidants include, but are not limited to, ascorbic acid, methionine, etc.

[0034] A therapeutically effective amount of the IDH1 inhibitor of the present invention can be administered to a subject in need thereof, such as a mammal (e.g., a human). The mode of administration is not particularly limited, and representative modes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, or intraperitoneal injection), and topical administration. Accordingly, the compound of formula I of the present invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, topical dosage forms, or external dosage forms.

[0035] The therapeutically effective amount of the present invention refers to the effective dosage considered pharmaceutically, that is, the amount of the active compound (i.e., the compound of Formula I) is sufficient to significantly improve the condition without causing serious side effects. The daily dosage of the compound of Formula I is generally 0.01-1000 mg / Kg, preferably 0.01-500 mg / Kg, or 0.5-200 mg / Kg, or 0.5-180 mg / Kg, or 0.5-150 mg / Kg, or 0.5-120 mg / Kg, or 0.5-100 mg / Kg, or 0.5-50 mg / Kg, or 0.5-40 mg / Kg, or 0.5-30 mg / Kg, and most preferably 0.5-25 mg / Kg. Exemplary effective dosages include, for example, 0.5 mg / Kg, 0.75 mg / Kg, 0.95 mg / Kg, 1 mg / Kg, 1.25 mg / Kg, 1.5 mg / Kg, 1.75 mg / Kg, 2 mg / Kg, 2.5 mg / Kg, 2.75 mg / Kg, 3 mg / Kg, 3.25 mg / Kg, 3.5 mg / Kg, 3.75 mg / Kg, 4 mg / Kg, 4.25 mg / Kg, 4.5 mg / Kg, 4.75 mg / Kg, 5 mg / Kg, 5.25 mg / Kg, 5.5 mg / Kg, 5.75 mg / Kg, 6 mg / Kg, 6.25 mg / Kg, 6.5 mg / Kg, 6.75 18mg / Kg, 19mg / Kg, 20mg / Kg, 21mg / Kg, 22mg / Kg, 23mg / Kg, 24mg / Kg, 25mg / Kg. It can be administered as a single dose once daily, can be administered multiple times daily, or can be used at intervals.

[0036] In certain embodiments, the present invention assesses improvement in neurological function using a neurological function scoring system, specifically the Jager method (5-point scale), with the following scoring criteria: 0: no symptoms; 1: tail paralysis or mild balance loss; 2: hind limb weakness, partial paralysis, or severe balance loss leading to spontaneous falls; 3: complete hind limb paralysis or very severe balance loss, inability to walk; 4: paralysis of both front and rear limbs, or inability to move the body to another position; 5: moribund. If symptoms fall between the two scores, an additional ±0.5 point may be assigned.

[0037] Joint application

[0038] One aspect of the present invention provides the use of an IDH1 inhibitor in the preparation of a medicament for treating demyelinating diseases of the central nervous system in combination with other drugs.

[0039] In the present invention, the other drugs include but are not limited to glucocorticoids (such as but not limited to methylprednisolone, dexamethasone, prednisone, etc.), immunomodulators (such as but not limited to interferon β, glatiramer acetate, cyclophosphamide, azathioprine, teriflunomide, fingolimod, siponimod, cladribine, etc.), monoclonal antibodies (such as but not limited to natalizumab, ocrelizumab, alemtuzumab, ofatumumab, etc.), etc.

[0040] Example 1

[0041] The following exemplifies that HY12475 can improve the clinical score of neurological function in EAE mice.

[0042] 1. Experimental Methods

[0043] 1.1 Experimental Grouping

[0044] Experimental autoimmune encephalomyelitis (EAE) is a classic animal model for studying demyelinating diseases of the central nervous system, including multiple sclerosis. Its pathological features closely resemble those of human disease, including myelin destruction and motor dysfunction mediated by various immune cells. Six- to eight-week-old female C57BL / 6 mice were selected and acclimated for one week to establish the EAE model. The mice were then randomly divided into a healthy control group, an EAE group, an EAE + HY12475 low-dose group, and an EAE + HY12475 high-dose group.

[0045] 1.2 Modeling method

[0046] MOG was washed with saline 35-55 The peptide was diluted to prepare a 10 mg / ml solution. Complete Freund's adjuvant (containing 1 mg / ml inactivated Mycobacterium tuberculosis H37Ra) was added at a volume ratio of 1:1, and inactivated Mycobacterium tuberculosis H37Ra was added to make the final concentration reach 4 mg / ml. Each mouse required 400 μg of tuberculin and MOG. 35-55250μg, complete Freund's adjuvant 0.05ml. The mixture was placed in a 5ml centrifuge tube, shaken at high speed for 20 seconds, then ice bathed for 2 minutes, and cycled 20 times. An oil-in-water immune antigen dilution mixture was formed, which was divided into 1ml syringes to remove all bubbles in the liquid. After the mice were anesthetized and fixed, subcutaneous injections were performed at any four points on both sides of the spine on the back of the mice, 0.1ml each. Subsequently, 500ng of pertussis toxin (PTX) was given to the mice by intraperitoneal injection on the 0th day of immunization (2h after modeling) and the 2nd day (48h). Neurological function scores were then performed on each group of mice every day.

[0047] 1.3 Drug intervention

[0048] HY12475 was purchased from MCE Company. The EAE+HY12475 low-dose group was given 10 mg / kg·day HY12475 intraperitoneal injection, and the high-dose group was given 20 mg / kg·day HY12475 intraperitoneal injection ( Figure 1 ), the EAE group and the healthy control group were intraperitoneally injected with the same volume of the solvent (DMSO) as the experimental group.

[0049] 2. Experimental Results

[0050] The results are as follows Figure 2 As shown, intraperitoneal injection of HY12475 significantly reduced the clinical score of EAE. These results indicate that inhibition of IDH1 by HY12475 has a significant effect on improving the disability progression of EAE, a classic model of multiple sclerosis.

[0051] Example 2

[0052] The following exemplifies the ability of HY12475 to alleviate weight loss in EAE mice.

[0053] 1. Experimental Methods

[0054] The modeling method and administration method were the same as those in Example 1. The body weight of mice in each group was monitored daily after modeling.

[0055] 2. Experimental Results

[0056] The results are as follows Figure 3 As shown, mice in the EAE group experienced significant weight loss after onset of the disease, but after treatment with HY12475, the extent of weight loss was significantly reduced, reaching statistical significance between days 17 and 20. These results suggest that inhibiting IDH1 with HY12475 has a significant therapeutic effect on weight loss in EAE.

[0057] Example 3

[0058] The following exemplifies the ability of HY12475 to improve demyelination in the lumbar enlargement of the spinal cord in EAE mice.

[0059] 1. Experimental Methods

[0060] The modeling method and administration method were the same as those in Example 1. Samples were collected 20 days after modeling (i.e., at the peak of the disease), and the lumbar enlargement of the spinal cord was removed. After fixation with 4% paraformaldehyde, it was embedded in paraffin and made into 8 μm sections, which were then stained with Fast Blue.

[0061] Main steps: After dewaxing paraffin sections, place them in Granulin stain at room temperature overnight. The next day, place the sections and staining jar in a 55°C waterbath for 1 hour. Then, rinse the sections in 95% ethanol for 3 minutes to remove the stain. Differentiate the sections in lithium carbonate solution for 7 seconds and 70% ethanol for 30 seconds, repeating this process until the gray and white matter are clearly distinguishable. Rinse for 3 minutes. Stain with eosin solution for 3-5 minutes, rinse, dehydrate, clear, and mount the sections. Photograph under a microscope.

[0062] 2. Experimental Results

[0063] The results are as follows Figure 4 As shown in the results, compared to the control group, EAE mice showed significant demyelination in the lumbar enlargement of the spinal cord. However, treatment with HY12475 significantly improved this demyelination. These results suggest that inhibiting IDH1 through HY12475 can improve demyelination in the lumbar enlargement of the spinal cord in EAE, demonstrating a promising therapeutic effect.

[0064] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may be modified or some of the technical features thereof may be replaced with equivalents. Such modifications or replacements do not deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. Use of IDH1 inhibitors in the preparation of drugs for improving or treating demyelinating diseases of the central nervous system.

2. Use of the IDH1 inhibitor according to claim 1 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The IDH1 inhibitor includes a compound shown in Formula I:

3. Use of the IDH1 inhibitor according to claim 1 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The improvement or treatment of the central nervous system demyelinating disease includes at least one of the following situations: (1) Inhibit myelin destruction and / or improve demyelination; (2) Improve or enhance neurological function; (3) Improve motor dysfunction; (4) Slow down weight loss.

4. Use of the IDH1 inhibitor according to claim 1 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The central nervous system demyelinating disease includes multiple sclerosis, autoimmune encephalomyelitis or neuromyelitis optica spectrum disorder.

5. Use of the IDH1 inhibitor according to claim 1 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The medicament further includes a pharmaceutically acceptable carrier.

6. Use of the IDH1 inhibitor according to claim 5 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The pharmaceutically acceptable carrier includes at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative, and an antioxidant.

7. Use of the IDH1 inhibitor according to claim 1 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The improvement or treatment is achieved by administering a therapeutically effective amount of the drug to a subject in need thereof.

8. Use of the IDH1 inhibitor according to claim 7 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The subject includes a mammal.

9. Use of the IDH1 inhibitor according to claim 7 in the preparation of a medicament for improving or treating a demyelinating disease of the central nervous system, characterized in that: The therapeutically effective amount is 0.01-1000 mg / Kg.

10. Use of IDH1 inhibitors in the preparation of drugs for combined treatment of demyelinating diseases of the central nervous system with other drugs.

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