WO2022108390A1 - Composition pharmaceutique pour la prévention ou le traitement de troubles immunitaires dans lesquels l'expression de smile est réduite, contenant du biguanide en tant que principe actif - Google Patents
Composition pharmaceutique pour la prévention ou le traitement de troubles immunitaires dans lesquels l'expression de smile est réduite, contenant du biguanide en tant que principe actif Download PDFInfo
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- WO2022108390A1 WO2022108390A1 PCT/KR2021/017097 KR2021017097W WO2022108390A1 WO 2022108390 A1 WO2022108390 A1 WO 2022108390A1 KR 2021017097 W KR2021017097 W KR 2021017097W WO 2022108390 A1 WO2022108390 A1 WO 2022108390A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- the present invention relates to a pharmaceutical composition for the prevention or treatment of immune diseases in which SMILE expression is reduced, comprising biguanide as an active ingredient.
- the human body consists of about 200 joints. Joints are the places where bones meet. Joints are composed of cartilage, joint capsule, synovial membrane, ligaments, tendons, muscles, etc. so that bones can move smoothly between bones, and they serve to absorb shocks caused by movement. Inflammatory diseases appearing in these joints are chronic joint rheumatism, which is understood to be caused by autoimmunity, infectious arthritis caused by bacterial infection, degenerative arthritis in which degeneration or destruction of articular cartilage or bones due to various causes, and degenerative changes in connective tissue. It can be broadly classified into crystalline arthritis, in which soluble metabolites are deposited as crystals in the connective tissue around the joint.
- rheumatoid arthritis and degenerative arthritis are characterized by infiltration of inflammatory cells into the joint synovial tissue, which is mediated by chemokines.
- Chemokines such as monocyte chemoattractant protein-1 (MCP-1) are expressed in the synovial tissue of arthritis, and these are known to be produced in synovial fibroblasts.
- MCP-1 monocyte chemoattractant protein-1
- Excess MCP-1 produced by arthritis invites monocytes and macrophages to the site of inflammation, and by activating these cells, it promotes the production of inflammatory cytokines, thereby exacerbating inflammation.
- Rheumatoid arthritis and degenerative arthritis are chronic systemic inflammatory diseases that cause symmetrical and polyarthritis and joint damage and deformation. If treatment for such arthritis is not received, the progress is poor and joint function is impaired. In Korea, it is estimated that about 1% of the total population is suffering from rheumatoid arthritis.
- Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by joint inflammation, and joint inflammation continuously infiltrates articular cartilage and bone tissue, resulting in erosion of these tissues.
- type 2 collagen a major component of the joint, is well known, and when it is injected into mice having a specific histocompatibility antigen, rheumatoid arthritis is induced (LK Myers et al., Life Sci., 19:1861-1878 (1997)).
- Rheumatoid arthritis is a stage in which inflammation of the synovial membrane spreads to the joint capsule, ligament, and tendon (stage 1), and the joint space is narrowed due to the gradual destruction of the joint cartilage. It progresses to a stage in which the tension of the joint membrane and ligaments is lost (stage 2), a stage in which inflammation invades the bone and partial erosion of the bone occurs (stage 3), and a stage in which joint function is lost (stage 4).
- stage 2 a stage in which inflammation invades the bone and partial erosion of the bone occurs
- stage 4 a stage in which joint function is lost
- the main causes of rheumatoid arthritis are gradually being identified, and genetic factors, infections, and hormone abnormalities are considered to be the causative factors. Due to these causative factors, the phenomenon of 'autoimmunity' occurs.
- Autoimmunity is a phenomenon in which chronic inflammation occurs multiple times and continuously in various parts of the body due to abnormalities in the immune regulation function of our body.
- Autoimmune disease is a normal immune system that distinguishes one's own cells or tissues (self-antigen) from foreign microorganisms (non-self-antigen) and does not respond to the self-antigen or exhibits no immune function even if it responds. It refers to a condition in which lymphocytes respond strongly to self-antigens and cause tissue damage by displaying this abnormal immune response.
- ankylosing spondylitis (AS) is not clearly identified, it is assumed that genetic abnormalities and infectious immune-inflammatory responses are involved in the pathogenesis, similar to systemic rheumatoid diseases such as rheumatoid arthritis and systemic lupus erythematosus. The specific cause has not been elucidated. It is assumed that the histocompatibility antigen gene called 'HLA-B27' is genetically involved in the pathogenesis, and other recent studies suggest that ERAP1 (endoplasmic reticulumaminopeptidase 1) and IL23R (interleukin 23 receptor) genes are involved.
- ERAP1 endoplasmic reticulumaminopeptidase 1
- IL23R interleukin 23 receptor
- the first is to reduce weight by burning excess fat
- the second is to improve metabolic imbalance.
- Patients with abdominal obesity are often associated with pathological conditions such as X-syndrome (insulin resistance, type 2 diabetes mellitus, high blood pressure and abnormal lipid metabolism) and are a strong risk factor for premature arteriosclerosis, ischemic heart disease and cerebrovascular disease.
- pathological conditions such as X-syndrome (insulin resistance, type 2 diabetes mellitus, high blood pressure and abnormal lipid metabolism) and are a strong risk factor for premature arteriosclerosis, ischemic heart disease and cerebrovascular disease.
- X-syndrome insulin resistance, type 2 diabetes mellitus, high blood pressure and abnormal lipid metabolism
- innate immunity innate immunity
- acquired immunity acquired immunity
- B cells innate immunity
- T cells antigen-presenting cells
- B cells and T cells effector cells.
- B cells are involved in humoral immunity that secretes antibodies
- T cells are mainly responsible for cellular immunity and are cytotoxic T cells. It is classified into cytotoxic T cells and helper T cells.
- the immune system controls a specific immune response to an autoantigen, and in some cases also suppresses an immune response to a foreign antigen.
- T cells are generated in the thymus of the human body and differentiate into T cells with unique characteristics through a series of differentiation processes. differentiated into helper cells (Th2).
- Th2 cells helper cells
- Th1 cells the main function of Th1 cells is involved in cell-mediated immunity
- Th2 cells are involved in humoral immunity
- these two cell populations maintain the balance of the immune system by checking each other so that they do not overactivate each other.
- Tregs immunoregulatory T cells
- Treg and adaptive Treg cell It is present at a frequency of 10%.
- Treg cells have the characteristic of controlling the inflammatory response by suppressing the function of abnormally activated immune cells, and many studies are being conducted to treat immune diseases by increasing the activity of Treg cells.
- Th17 cells are known to be formed through a process similar to the differentiation of Treg cells in the differentiation process of undifferentiated T cells. It has been found that Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases and accelerate disease progression by maximizing the signal of the inflammatory response.
- An object of the present invention is to provide a pharmaceutical composition for preventing or treating immune diseases caused by underexpression of the SMILE gene, including a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of immune diseases accompanied by metabolic abnormalities comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating immune diseases having refractory response to a TNF-alpha inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. .
- Another object of the present invention is to provide a method for treating immune diseases accompanying metabolic abnormalities, including administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- Another object of the present invention the step of administering to the subject a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof To provide a method for treating a disease.
- Another object of the present invention the step of administering to the subject a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, immune disease caused by underexpression of the SMILE gene, including; to provide a treatment method for
- the present invention provides a pharmaceutical composition for preventing or treating immune diseases caused by underexpression of the SMILE gene comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof do.
- the present invention provides a pharmaceutical composition for the prevention or treatment of immune diseases accompanied by metabolic abnormalities comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention provides a pharmaceutical composition for preventing or treating immune diseases having refractory response to a TNF-alpha inhibitor comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for treating immune diseases accompanied by metabolic abnormalities, comprising administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the step of administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; treatment methods are provided.
- the present invention comprising the step of administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, for the treatment of immune diseases caused by underexpression of SMILE gene provide a way
- the present invention confirmed that the decrease in the expression of SMILE induces autoimmune diseases such as arthritis, ankylosing spondylitis, and inflammatory bowel disease. Accordingly, it was confirmed that the TNF-alpha inhibitor exhibited refractory. Therefore, it was confirmed that, upon treatment with the biguanide (SD282) of the present invention, the expression of SMILE was increased to improve TNF-alpha inhibitor refractory as well as induce an increase in beneficial microbiome and increase in mitochondrial function. Therefore, it is confirmed that it is excellent in the treatment of not only arthritis, ankylosing spondylitis, inflammatory bowel disease, but also autoimmune diseases accompanied by metabolic abnormalities, and thus can be usefully used in related industries.
- autoimmune diseases such as arthritis, ankylosing spondylitis, and inflammatory bowel disease. Accordingly, it was confirmed that the TNF-alpha inhibitor exhibited refractory. Therefore, it was confirmed that, upon treatment with the biguanide (SD282) of the present invention, the expression of
- FIG. 1 is a diagram illustrating the expression of SMILE in a mouse animal model induced with metabolic dysfunction (Obese CIA) of the present invention by immunohistochemical staining (A: splenocyte immunohistochemistry, B: SMILE expression quantification).
- FIG. 2 is a diagram confirming the effect of biguanide in the metabolic arthritis (Obese CIA) induced mouse animal model of the present invention refractory to TNF-alpha inhibitor by the expression of IgG2a.
- FIG. 3 is a mouse animal model induced with metabolic arthritis (Obese CIA) of the present invention shows the refractory effect of TNF-alpha inhibitors, and the joint protective effect of biguanide in metabolic arthritis with H&E and safranin O ( safranin O) staining (A: H&E and safranin O staining optical microscopy, B: arthritis score and quantification of tissue damage).
- Figure 4 is a mouse animal model induced with metabolic arthritis (Obese CIA) of the present invention shows the refractory to TNF-alpha inhibitor, and the effect of biguanide in metabolic arthritis using immunohistochemical staining IL- 17 is a diagram observed by expression (A: joint immunohistochemical staining confirmation, B: IL-17 quantification).
- Figure 5 is a diagram confirming the increase in the expression of SMILE by the immunohistochemical staining method by administering biguanide in the mouse animal model induced with metabolic arthritis (Obese CIA) of the present invention (A: spleen immunohistochemical staining confirmation, B: SMILE quantification).
- FIG. 6 is a diagram confirming that collagen antibody induced arthritis is induced in SMILE overexpressing mice of the present invention, and that SMILE overexpression exhibits arthritis improvement and protective effects.
- FIG. 7 is a diagram confirming the improvement and protective effect of SMILE overexpression on arthritis by inducing collagen antibody induced arthritis in SMILE overexpressing mice of the present invention by H&E and safranin O staining.
- FIG. 8 is a diagram confirming the distribution of immunomodulatory cell subtypes according to SMILE overexpression by inducing collagen antibody induced arthritis in SMILE overexpressing mice of the present invention by flow cytometry.
- SMILE peripheral blood mononuclear cells
- FIG. 10 is a diagram showing the process of making a mouse model of arthritis due to obesity and a drug administration schedule.
- 11 is a diagram confirming the arthritis treatment effect of SD282 administration in an obese arthritis animal model as an arthritis index.
- 12 is a view confirming the effect of inhibiting joint tissue destruction by the administration of SD282 in an animal model of obese arthritis.
- FIG. 13 is a diagram confirming the inhibition mechanism of obesity arthritis of SD282 by confirming the activity of T helper cells:
- 15 is a diagram showing histochromatographic analysis of changes in SMILE expression by SD282 administration in an animal model of obese arthritis.
- 16 is a diagram confirming the mitochondrial reactive oxygenation inhibitory effect of SD282 in an animal model of obese arthritis.
- 17 is a diagram confirming changes in mitochondrial potential in pathogenic immune cells by SD282 administration in an animal model of obesity and arthritis.
- FIG. 18 is a diagram confirming the mRNA expression and protein expression change of Grim19 in pathogenic immune cells by SD282 administration in an animal model of obese arthritis.
- Ndufb5 Uqcrb
- Cycs genes related to mitochondrial Oxphos complex function
- FIG. 20 is a diagram confirming whether mitochondrial respiration is regulated in pathogenic immune cells by SD282 administration in an animal model of obesity and arthritis.
- 21 is a diagram confirming whether the microbiome is recovered by SD282 administration in an animal model of obesity and arthritis.
- 22A is a diagram illustrating inflammation relief when SD282 is administered to a model intervertebral disc of intractable ankylosing spondylitis accompanied by metabolic abnormalities.
- 22B is a diagram showing AF scores when SD282 is administered to an intervertebral disc in a model of intractable ankylosing spondylitis accompanied by metabolic abnormalities.
- 22c is a diagram showing the NP score when SD282 is administered to a model of intractable ankylosing spondylitis model with metabolic abnormalities.
- 23A is a diagram showing the inhibition of inflammation in the small intestine when SD282 is administered to the small intestine in a model of intractable ankylosing spondylitis accompanied by metabolic abnormalities.
- 23B is a diagram showing the degree of inflammatory infiltrate in the small intestine in an intractable ankylosing spondylitis model accompanied by metabolic abnormalities.
- 23C is a diagram showing the degree of epithelial damage in the small intestine in an intractable ankylosing spondylitis model accompanied by metabolic abnormalities.
- 24 is a diagram showing the regulation of inflammatory immune cells in a model of refractory ankylosing spondylitis accompanied by metabolic abnormalities.
- 25 is a diagram confirming the SMILE expression of biguanide by immunohistochemical staining in inflammatory bowel disease-induced mice (A: immunohistochemical staining result, B: SMILE expression quantification).
- the present invention provides a pharmaceutical composition for preventing or treating immune diseases caused by underexpression of the SMILE gene, which includes a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- prevention refers to any action that suppresses the symptoms of a specific disease or delays the progression by administration of the composition of the present invention.
- treatment refers to any action that improves or beneficially changes the symptoms of a specific disease by administration of the composition of the present invention.
- the pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient.
- the adjuvant may be used without limitation as long as it is known in the art, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the effect.
- the pharmaceutical composition according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field.
- Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- the pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. .
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
- Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc.
- compositions for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories.
- non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
- base of the suppository witepsol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
- composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
- the dosage of the pharmaceutical composition according to the present invention is selected in consideration of the individual's age, weight, sex, physical condition, and the like. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 ⁇ g/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 ⁇ g/ml, it may be toxic to the human body.
- the immune disease caused by the underexpression of the SMILE gene may be arthritis, ankylosing spondylitis, or inflammatory bowel disease, but is not limited thereto.
- the immune disease accompanied by the metabolic abnormality may further include having refractory to a TNF-alpha inhibitor.
- the present invention provides a pharmaceutical composition for the prevention or treatment of immune diseases accompanied by metabolic abnormalities comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the immune disease accompanying the metabolic abnormality may be arthritis accompanied by the metabolic abnormality, preferably rheumatoid arthritis, but is not limited thereto.
- the rheumatoid arthritis may be immunosuppressant refractory refractory rheumatoid arthritis.
- the immune disease accompanying the metabolic abnormality may be ankylosing spondylitis accompanied by the metabolic abnormality.
- the above target may be obesity.
- the immune disease is inflammatory bowel disease, Behcet's disease, polymyositis or dermatomyositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary liver cirrhosis, dermatomyositis, good piecher Syndrome, autoimmune meningitis, Sjogren's syndrome, lupus, Addison's disease, alopecia areata, autoimmune hepatitis, autoimmune mumps, Crohn's disease, insulin-dependent diabetes mellitus, dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves disease, Guillain-Barré syndrome , Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, sarcoidosis, sclero
- the immune disease accompanied by the metabolic abnormality may be a decrease in the SMILE gene.
- composition may increase the expression of the SMILE gene.
- the composition induces the expression of the SMILE gene
- the composition may inhibit inflammation through inhibition of expansion of the annulus fibrosus of the intervertebral disc and inhibition of infiltration of the nucleus pulposus (Nucleus Fibrosus).
- the composition may be to modulate lymphocyte inflammatory immune cells.
- the composition may inhibit the destruction of joint synovial tissue (synovium).
- the composition may promote or increase the activity of regulatory T cells (Regulatory T cells: Treg), and decrease or inhibit the activity of Th17 cells, which are pathogenic cells.
- regulatory T cells Regulatory T cells: Treg
- Th17 cells which are pathogenic cells.
- the composition may inhibit autoantibody activity, and the autoantibody is
- it may be an autoantibody to citrullinated vimentin, but is not limited thereto.
- the composition may be to promote the expression of Grim19 (gene associated with retinoid-IFN-induced mortality 19).
- the composition may inhibit mitochondrial ROS activity.
- the composition may be to improve mitochondrial dysfunction, the mitochondrial dysfunction is mitochondrial oxidative phosphorylation complex (Oxphos complex) function-related gene expression abnormality, mitochondrial respiration inhibition, mitochondrial membrane potential decrease And it may be one or more selected from the group consisting of reduced mitochondrial activity.
- mitochondrial dysfunction is mitochondrial oxidative phosphorylation complex (Oxphos complex) function-related gene expression abnormality, mitochondrial respiration inhibition, mitochondrial membrane potential decrease
- Oxphos complex mitochondrial oxidative phosphorylation complex
- the composition may be to increase the beneficial microbiome in the intestine, preferably, Akkermansia muciniphilia in the intestine.
- the present invention provides a pharmaceutical composition for the prevention or treatment of immune diseases having refractory response to a TNF-alpha inhibitor comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- the immune disease having a refractory response to the TNF-alpha inhibitor may be arthritis, preferably rheumatoid arthritis.
- the metabolic abnormality may be obesity.
- the immune disease having a refractory response to the TNF-alpha inhibitor may be an immune disease in which the SMILE gene is reduced.
- the immune disease may be a decrease in the SMILE gene in the spleen tissue of the patient.
- the composition may increase the expression of the SMILE gene to prevent or treat immune diseases.
- the present invention provides a method for treating immune diseases accompanied by metabolic abnormalities, comprising administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
- the treatment method of the present invention comprises administering to an individual a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically salt thereof.
- a specific therapeutically effective amount for a particular subject will depend on the type and extent of the response to be achieved, the specific composition, including whether other agents are used, if necessary, the subject's age, weight, general health, sex and diet, time of administration; It is preferable to apply differently depending on various factors including the route of administration and secretion rate of the composition, the duration of treatment, the drug used together with or concurrently with the specific composition, and similar factors well known in the pharmaceutical field.
- the daily dose is 0.0001 to 100 mg/kg, preferably 0.01 to 100 mg/kg, based on the amount of the pharmaceutical composition of the present invention, and may be administered 1 to 6 times a day.
- the dose or dosage of each active ingredient should be such that the side effects do not occur by including the content of each active ingredient too high. Therefore, it is preferable to determine the effective amount of the composition suitable for the purpose of the present invention in consideration of the foregoing.
- the subject is applicable to any mammal, and the mammal includes not only humans and primates, but also domestic animals such as cattle, pigs, sheep, horses, dogs and cats.
- the compound of Formula 1 or a salt thereof of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
- the step of administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof; treatment methods are provided.
- the present invention comprising the step of administering to an individual a pharmaceutically effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, for the treatment of immune diseases caused by underexpression of SMILE gene provide a way
- SMILE small heterodimer partner-interacting leucine zipper protein
- a high fat diet of 60 kcal is self-feeding from one week before inducing arthritis in 7-week-old male DBA1/J normal mice, and the high fat diet is performed until the end of the experiment.
- 100 ⁇ g of type II collagen was mixed with CFA (Complete Freud's adjuvant) and injected into the tail epidermis (first immunization). adjuvant) and then injected into the tail to prepare an animal model of metabolic arthritis (obese arthritis, Obese CIA).
- a normal control group (average body weight: 20 g, wild type) administered with a normal diet was used, and biguanide (SD-282) was administered to the metabolic arthritis animal model. Also, in general, etanercept, a TNF-alpha inhibitor administered to treat arthritis, was administered and classified as a positive control group (Enbrel).
- SMILE small heterodimer partner-interacting leucine zipper protein
- TNF-alpha inhibitor of the animal model prepared in Example 1-1, and to confirm that biguanide (SD-282) is effective in TNF-alpha refractory obesity arthritis, anti-collagen Expression of mouse IgG2a having an effect was confirmed.
- IgG2a When IgG2a is overexpressed, it is known to cause arthritis by decomposing collagen, and is stimulated by TNF-alpha, so a TNF-alpha inhibitor is generally administered to inhibit IgG2a.
- IgG2a was measured in the spleen of a sacrificed mouse using an ELISA kit.
- mice were evaluated according to the following criteria in order to evaluate the joint inflammation score before sacrifice.
- Hind paws When there is no erythema and there is no difference from normal mouse paws visually, the bone shape is clearly and normally confirmed by looking at the outside.
- Hindfoot Swelling of one toe/or marked erythema without swelling on the sole of the foot/or slight swelling of the dorsum of the foot, sole or heel.
- Forefoot Swelling of one toe and/or marked erythema without swelling on the sole of the foot.
- Hind foot (with erythema) When two toes are swollen / When one or two toes are swollen, or the top of the foot, sole or heel is slightly rounded.
- Forefoot (with erythema) When two toes are swollen / When one or two toes are swollen or the ankle is swollen.
- Hind foot (with erythema) When 1 to 4 toes are swollen, or the instep, sole or heel is swollen as a whole / The shape of the calcaneus is hardly revealed and the instep of the sole of the foot is swollen up to the heel and ankle, so it looks slightly plump due to inflammatory edema.
- Forefoot (with erythema) One to four toes are swollen or the ankle is thickened due to an increase in inflammatory tissue in the ankle area.
- Hind paws Erythema is almost developmental / swollen 3 or more toes, the feet are swollen all over, the erythema and swelling are very severe, and the whole body is plump.
- IL-17 is an interleukin that induces inflammation, and is expressed when the differentiation of IL-17-positive cells is promoted to induce inflammation.
- biguanide SD-282
- TNF-alpha refractory obesity arthritis in order to check whether biguanide (SD-282) is effective on TNF-alpha refractory obesity arthritis, to check whether it inhibits IL-17-positive cells in the joint tissue Joints were confirmed by histochemical staining.
- TNF-alpha inhibitor refractory obesity arthritis animal model prepared in Example 1-1, to determine whether biguanide induces the expression of SMILE, the TNF-alpha inhibitor refractory obesity arthritis animal model (Obese CIA) was divided into two groups. , and biguanide was administered to the experimental group at a concentration of 50 mg/kg, and the control group was treated with the same amount of physiological saline. Thereafter, the mice were humanely sacrificed, the spleen was removed, and the expression of SMILE was confirmed by immunohistochemical staining of the extracted spleen.
- SMILE overexpression mice were prepared. Specifically, SMILE (small heterodimer partner-interacting leucine zipper protein) gene (SEQ ID NO: 1) was cloned into the EcoRI and Xho I restriction enzyme sites of the pcDNA3 vector to construct a plasmid overexpressing SMILE. DNA purification for microinjection was completed by single-cutting the SMILE plasmid with Fspl. After microinjection 19 days later, live offspring were obtained, and positive SMILE Tg mice (SMILE Transgenic, SMILE Tg) expressing SMILE were obtained after genotype progress through pup tailcutting. A mock was used as a control (C57BL/6).
- SEQ ID NO: 1 small heterodimer partner-interacting leucine zipper protein
- Example 4-1 the collagen antibody, IgG2a, was injected into the joint to induce collagen antibody-induced arthritis to induce arthritis (CAIA+C57BL/6) and SMILE overexpression group (CAIA+SMILE) ) was observed for arthritis induction and protective effects for 10 days. After the arthritis was induced, the arthritis score of the mice was evaluated according to the same criteria as in Example 2-2.
- the mouse animal model prepared in Example 4-1 was humanely sacrificed after the end of the experiment, and the spleen was removed. After that, each of the extracted spleens was subjected to flow cytometry analysis. Specifically, the extracted spleen was treated with LPS 100ng/ml to activate immune cells, and then markers of CD4 T cells and B220-positive cells were analyzed to analyze immune regulatory cell subtypes according to SMILE overexpression.
- T-regulator cells were increased as a subtype of immunoregulatory cells in the SMILE overexpressing mouse animal model, and B-regulator cells (Bregs) were Immature B cells known to have a function increased.
- B-regulator cells were Immature B cells known to have a function increased.
- the mature B (mature B) cells and plasma B cells (plasma B) having an antibody-producing ability are reduced.
- mice were fed a 60Kcal high-calorie feed (high-fat diet) to induce obesity and at the same time to induce rheumatoid arthritis at a concentration of 4mg/ml.
- high-fat diet high-fat diet
- rheumatoid arthritis at a concentration of 4mg/ml.
- CFA complete freud's adjuvant
- the solution was mixed with sterilized tertiary distilled water at a ratio of 1:10 (solution: distilled water), and then 200 ⁇ l of the solution was first inoculated into the abdominal cavity.
- a mixed solution of 4 mg of type 2 collagen and IFA incomplete freud's adjuvant was prepared in the same manner as for the first inoculation, and then divided into two parts at the base of the tail and intradermally (intradermally). ) was inoculated second with 100 ⁇ l each.
- Femurs and tibias were collected from mice at the time of sacrifice of the obesity-arthritis-inducing group and the obesity-arthritis-inducing +SD282 treatment group of Example 6, and then the separated joints were fixed with 10% formalin and calcified from the bones. After removal, a block was prepared with paraffin. A joint section (7um) was prepared from this, and the joint section was stained with hematoxylin and eosin (H&E). In addition, Safranin O (Safranin O) staining, a staining method that can determine the degree of destruction of cartilage, was performed to observe the shape of the cartilage, and the cartilage damage and bone damage were scored.
- spleen cells were isolated from each of the obesity-arthritis-induced group and the SD282-treated group after the induction of obesity-arthritis-induced inflammation, and the activity of T helper cells was compared and analyzed.
- the SD282-treated obese arthritis model mice showed a decrease in Th17 (IL-17 secreting T cells), which is known as a pathogenic cell, and an increase in Treg, an immunoregulatory cell, compared to the control group ( FIG. 13 ).
- Th17 IL-17 secreting T cells
- Treg an immunoregulatory cell
- citrullinated vimentin acts as an autoantigen in rheumatoid arthritis
- the expression level in the synovial tissue of the animal model of obese arthritis by SD282 treatment was confirmed with a fluorescence microscope through immunohistochemical staining. While the expression of citrulline non-mentin in the joint synovial tissue was significantly increased compared to that of the normal control group, it was shown that the expression of trulline non-mentin was significantly decreased when SD282 was administered to an animal model of obese arthritis ( FIG. 14 ). Through this, it was confirmed that SD282 can inhibit the activity of autoantibodies generated in severe rheumatoid arthritis induced by obesity.
- SMILE small heterodimer partner-interacting leucine zipper protein
- SD282 can regulate not only disease activity, but also immune cell activity, autoantigen regulation, and mitochondrial function regulation in severe rheumatoid arthritis disease accompanied by metabolic abnormalities.
- CD4+ T cells isolated from normal mouse spleen were cultured for 3 days under Th17 cell differentiation conditions.
- metformin Metalformin
- SD282 were treated with 500uM or 100uM, respectively.
- JC1 staining was performed to measure the mitochondrial membrane potential in cultured Th17 cells.
- PE fluorescence increased, confirming an increase in the mitochondrial membrane potential, which showed a remarkable effect at a much lower concentration than metformin (FIG. 17). Therefore, it was confirmed that SD282 can improve the function of mitochondria.
- Girm19 (gene associated with retinoid-IFN-induced mortality 19) is a naturally occurring protein in vivo as an inhibitor of STAT3, a pathogen that enters the nucleus It is known that STAT3 in the cytoplasm moves into the mitochondria by binding to Grim19 in the cytoplasm). Accordingly, the expression change of Grim19 was evaluated to analyze the regulation of mitochondrial function by SD282. Specifically, CD4+ T cells isolated from normal mouse spleen were cultured under Th17 cell differentiation conditions for 3 days, and at the same time, SD282 was treated with 100 ⁇ M each, and real-time reverse transcriptase chain reaction and SDS-PAGE analysis were performed.
- mitochondrial respiration was measured to determine the effect on mitochondrial function in rheumatoid arthritis mouse spleen cells activated by anti CD3 and LPS.
- SD282 100uM or metformin (Met) as a positive control
- FCCP 3 ⁇ M
- OCR oxygen consumption rate
- SD282 was orally administered to mice with osteoarthritis at 50 mg/kg, and Fecal was collected from the mice on the last day of sacrifice.
- Akkermansia muciniphilia a flora that increases the immune regulation function
- SD5282 FIG. 21
- Example 17 Ankylosing spondylitis animal model production method.
- SKG mice are mice in which ZAP70 is point mutated, and it is characterized by the activation of autoreactive T cells by continuous TCR signal transduction.
- Injection of ⁇ -glucan chemical Curdlan, which is a component of fungi, into the SKG mice exhibits tissue, immune and pathological characteristics similar to human ankylosing spondylitis.
- Ankylosing spondylitis model was prepared by dissolving Curdlan in saline at 15mg/ml and injecting 200ul each orally and intraperitoneally.
- Example 17 In the ankylosing spondylitis animal model prepared in Example 17, the control group and SD282 were administered to confirm the relief of inflammation in the intervertebral disc. In this experiment, Vehicle was used as a control.
- Ankylosing spondylitis animal model with metabolic abnormalities By oral administration of a control (Vehicle) and 50 mg/kg SD282 to an intervertebral disc, intervertebral disc inflammation, AF (Annulus Fibrosus, annulus fibrosus) score and NP (Nucleus Pulposus, disc) of the nucleus pulposus) score was confirmed.
- FIG. 22a inflammation was relieved in the group administered with SD282 to the intervertebral disc, and as a result of confirming the AF score, the degree of expansion of the annulus fibrosis was lowered in the group administered with SD282 (Fig. 22b), and the NP score was also administered with SD282.
- FIG. 22c the degree of inflammatory infiltration of the nucleus pulposus was significantly lower (FIG. 22c), so that the compound of the present invention was effective in treating ankylosing spondylitis.
- control group and SD282 50 mg/kg were orally administered to the ankylosing spondylitis animal model with metabolic abnormalities prepared in Example 1 to reduce inflammation, Inflammatory infiltrate (inflammatory penetration) and Epithelial damage (epithelial tissue damage) in the small intestine. Confirmed.
- FIG. 23A inflammation was relieved in the group administered with SD282 to the small intestine of ankylosing spondylitis animal model accompanied by metabolic abnormalities, and the group administered with SD282 showed a very high inflammatory infiltrate (inflammatory infiltrate) compared to the control group (Vehicle). It was confirmed that the lowering (FIG. 23b). In addition, as a result of checking the epithelial damage, the group administered with SD282 had a lower tissue damage (FIG. 23c), confirming that the compound of the present invention was excellent in treating ankylosing spondylitis.
- Inflammatory immune cell regulation was confirmed by administering the control group and SD282 to the ankylosing spondylitis animal model prepared in Example 17.
- Vehicle was used as a control.
- Ankylosing spondylitis animal model The control group (Vehicle) and SD282 were administered to the small intestine to confirm the lymphocyte inflammatory factors IL-17 and CD4 + .
- the compound of the present invention inhibited IL-17 and CD4 + in the group administered with SD282 in an ankylosing spondylitis animal model, confirming the therapeutic effect of the ankylosing spondylitis.
- an inflammatory bowel disease animal model was prepared. Specifically, 7-week-old male C57BL/6 mice were watered with 3% dextran sodium sulfate (DDS). Water was replaced with general drinking water on the 5th day. After that, biguanide was administered at a concentration of 50 mg/kg once a day for 8 weeks. As a control group, a vehicle group administered with physiological saline was used.
- DDS dextran sodium sulfate
- mice of Example 5-1 were humanely sacrificed after the end of the experiment, and intestinal tissues were removed.
- the excised intestinal tissue was sectioned and the expression of SMILE was confirmed by immunohistochemical staining.
- the present invention confirmed that the reduction in the expression of SMILE caused metabolic arthritis, and it was confirmed that the metabolic arthritis induced by the inhibition of SMILE was refractory to the TNF-alpha inhibitor. In addition, it was confirmed that in TNF-alpha inhibitor-refractory obesity arthritis, treatment with biguanide (SD282) suppressed the expression of IgG2a and IL-17, which was not improved with the TNF-alpha inhibitor.
- the compound SD282 of the present invention promotes the expression of an inflammatory response inhibitory gene, inhibits the destruction of joint synovial tissue, and regulates pathogenic cells and immunoregulatory cells.
- an inflammatory response inhibitory gene inhibits the destruction of joint synovial tissue, and regulates pathogenic cells and immunoregulatory cells.
- refractory rheumatoid arthritis refractory to TNFa inhibitors by inhibiting the decrease in mitochondrial function and increasing the microbiome.
- the expression of SMILE was effectively increased in the inflammatory bowel disease animal model.
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Abstract
La présente invention a déterminé qu'une réduction de l'expression de SMILE induit des maladies auto-immunes telles que l'arthrite, la spondylarthrite ankylosante et une affection abdominale inflammatoire. Par conséquent, il a été déterminé qu'un réfractaire aux inhibiteurs de TNF-alpha est présenté. Ainsi, il a été déterminé que par administration de biguanide (SD282) de la présente invention, l'expression de SMILE est augmentée de telle sorte qu'un réfractaire aux inhibiteurs de TNF-alpha est atténué et qu'une augmentation du microbiome utile et une augmentation de la fonction mitochondriale peuvent également être induites. Par conséquent, il a été déterminé que la présente invention est supérieure dans le traitement de l'arthrite, de la spondylarthrite ankylosante, d'une affection abdominale inflammatoire et de maladies auto-immunes accompagnées d'une anomalie métabolique, et peut ainsi être efficacement utilisée dans les industries pertinentes.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20200156184 | 2020-11-20 | ||
| KR10-2020-0156184 | 2020-11-20 | ||
| KR1020210083361A KR20230000792A (ko) | 2021-06-25 | 2021-06-25 | 면역억제제 불응하는 자가면역질환의 치료제로서의 sd282의 용도 |
| KR10-2021-0083361 | 2021-06-25 | ||
| KR10-2021-0141096 | 2021-10-21 | ||
| KR1020210141096A KR20230057091A (ko) | 2021-10-21 | 2021-10-21 | 바이구아나이드를 유효성분으로 포함하는 대사이상 동반 난치 강직성 척추염 치료용 조성물 |
| KR1020210160195A KR102504468B1 (ko) | 2020-11-20 | 2021-11-19 | 바이구아나이드를 유효성분으로 포함하는 smile 발현이 저하된 대사이상 난치 류마티스관절염 또는 염증성 장질환의 예방 또는 치료용 약학적 조성물 |
| KR10-2021-0160195 | 2021-11-19 |
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| WO2022108390A1 true WO2022108390A1 (fr) | 2022-05-27 |
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| PCT/KR2021/017097 WO2022108390A1 (fr) | 2020-11-20 | 2021-11-19 | Composition pharmaceutique pour la prévention ou le traitement de troubles immunitaires dans lesquels l'expression de smile est réduite, contenant du biguanide en tant que principe actif |
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Cited By (1)
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| WO2024143582A1 (fr) * | 2022-12-27 | 2024-07-04 | 가톨릭대학교 산학협력단 | Composition d'agent thérapeutique injectable à base de composé de biguanide pour le traitement d'une maladie articulaire |
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| US20130095140A1 (en) * | 2011-01-07 | 2013-04-18 | Elcelyx Therapeutics, Inc. | Biguanide Compositions and Methods of Treating Metabolic Disorders |
| WO2015167243A1 (fr) * | 2014-04-29 | 2015-11-05 | 가톨릭대학교 산학협력단 | Nouveau composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé |
| KR20190045513A (ko) * | 2017-10-24 | 2019-05-03 | 가톨릭대학교 산학협력단 | Sd282 화합물 또는 칼시뉴린 억제제를 포함하는 이식 거부 반응 또는 이식 후 면역 질환의 예방 및 치료용 조성물 |
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| US20130095140A1 (en) * | 2011-01-07 | 2013-04-18 | Elcelyx Therapeutics, Inc. | Biguanide Compositions and Methods of Treating Metabolic Disorders |
| WO2015167243A1 (fr) * | 2014-04-29 | 2015-11-05 | 가톨릭대학교 산학협력단 | Nouveau composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé |
| KR20190045513A (ko) * | 2017-10-24 | 2019-05-03 | 가톨릭대학교 산학협력단 | Sd282 화합물 또는 칼시뉴린 억제제를 포함하는 이식 거부 반응 또는 이식 후 면역 질환의 예방 및 치료용 조성물 |
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| GREMESE ELISA, TOLUSSO BARBARA, GIGANTE MARIA RITA, FERRACCIOLI GIANFRANCO: "Obesity as a Risk and Severity Factor in Rheumatic Diseases (Autoimmune Chronic Inflammatory Diseases)", FRONTIERS IN IMMUNOLOGY, vol. 5, 11 November 2014 (2014-11-11), XP055931650, DOI: 10.3389/fimmu.2014.00576 * |
| KIM SEUKUN, PARK SUNGYEON, KANG MINSOO, KO JESANG: "The role of small leucine zipper protein in osteoclastogenesis and its involvement in bone remodeling", BIOCHIMICA ET BIOPHYSICA ACTA, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, vol. 1867, no. 11, 1 November 2020 (2020-11-01), NL , pages 118827, XP055931653, ISSN: 0167-4889, DOI: 10.1016/j.bbamcr.2020.118827 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024143582A1 (fr) * | 2022-12-27 | 2024-07-04 | 가톨릭대학교 산학협력단 | Composition d'agent thérapeutique injectable à base de composé de biguanide pour le traitement d'une maladie articulaire |
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