KR101213070B1 - Composition for Prevention or Treatment of Rheumatoid Arthritis Comprising the Phospholipase D1 inhibitor - Google Patents

Abstract

The present invention relates to a composition for preventing or treating rheumatoid arthritis, comprising a phospholipase D1 inhibitor as an active ingredient. Phospholipase D1 inhibitors of the invention inhibit articular cartilage destruction, inhibit bone destruction and produce inflammatory cytokines (TNF-α, IL-1β, IL-6 and IFN-γ, MCP-1 and IL-17) Since inhibiting inflammation of the joint area by suppression shows an effect to significantly improve the symptoms of rheumatoid arthritis, the composition of the present invention comprising a phospholipase D1 inhibitor having such characteristics as an active ingredient is useful for preventing or treating rheumatoid arthritis Can be used.

Description

Composition for Prevention or Treatment of Rheumatoid Arthritis Comprising the Phospholipase D1 inhibitor}

The present invention relates to a composition for preventing or treating rheumatoid arthritis, comprising a phospholipase D1 inhibitor as an active ingredient, and a health functional food for preventing or treating rheumatoid arthritis.

Rheumatoid arthritis is an inflammatory autoimmune disease that occurs multiple times in multiple joints. In patients with arthritis, synovial membrane tissue of the joint is hyperplasia and is characterized by the formation of pannus and destruction of cartilage and bone. Macrophage, dendritic cells, and activated T lymphocytes and B lymphocytes migrate to the synovial tissue, and polymorphonuclear cells accumulate in the synovial fluid and on the surface of the cartilage for inflammation. Will cause. Inflammation of the synovial tissue is believed to be caused by T lymphocytes reactive to unknown autoantigens.

Nevertheless, T lymphocytes infiltrated most tissues show no activation marker on the cell surface and rarely express cytokines. In contrast, there are many cytokines derived from macrophage in synovial tissue and synovial fluid with rheumatoid arthritis symptoms. Such cytokines include interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), which are known to promote the growth of synovial fiber cells. These experimental results suggest that T lymphocytes are very important for causing inflammation of synovial tissue, and that subsequent inflammatory symptoms are maintained by cytokines derived from activated synovial cells.

Various clinical treatments for rheumatoid arthritis have been developed, which are divided into general conservative therapy, pharmacotherapy and surgical therapy. In general, the treatment of rheumatoid arthritis causes joint pain caused by chronic arthritis, joint deformation, and loss of function. Therefore, the aim of treatment is to return to normal life by suppressing pain and inflammation and minimizing joint loss of function. have.

Therapeutic methods currently in use are drug therapy, which depends on the symptoms of aspirin and nonsteroidal anti-inflammatory drugs, low-dose oral steroids, sulfasalzine, immunosuppressive agents (mesotrexate (MTX), imuran, etc.), Gold drugs (gold sodium thiosulfate), penicillamine (penicillamine), anti-malarial drugs (anti-malarials) such as (modifying disease anti-rheumatic drugs (DMARDs) are used. However, these drugs also slightly reduce the progression of arthritis, but they can have serious side effects, so only 5-15% of patients adhere to the drug after five years of treatment with DMARD. Tumor necrosis such as intra-articular steroid injections and anti-TNF antibodies such as etanercept (Enbrel ^TM , Wyeth), infliximab (Remicade ^TM , Centocor Ortho Biotech) and adalimumab (Humira ^TM , Abbott) factor blockade), interleukin-1 receptor antagonists such as anakinra (Kineret ^™ , Amgen), and anti-CD20 antibodies such as rituximab (Rituxan ^™ , Roche).

However, these drug therapies have the disadvantage that side effects such as gastrointestinal disorders, liver disorders, renal dysfunction, infection, etc. may occur, and are being developed mainly for suppressing inflammatory responses. Most of the arthritis treatments that have been developed and used to date have been designed to suppress the inflammatory response rather than being designed to protect cartilage and bone tissue of joint diseases, and in most cases, they have only limited therapeutic effects. there was. Therefore, the development of new materials for the prevention and treatment of rheumatoid arthritis is always required.

Phospholipase D (PLD) is an enzyme that breaks down phosphatidyl choline (PC) to produce phosphatidic acid (PA) and choline as secondary products, and the product PA is again a phosphatidic acid. It is degraded by phosphohydrolase (PPH) to produce diacylglycerol (DAG). These phosphatidic acid precursors are known to play an important role in cellular signaling and metabolic pathways. Phosphatidic acid is present at low levels in resting cells, and phospholipase D activity is known to be regulated by mechanisms that regulate cell vesicle migration, cell secretion, cell migration, cell survival and proliferation.

Phospholipase D exists in mammalian cells as two isozymes, PLD1 and PLD2, with slight differences in activity and function. In particular, phospholipase D1 inhibitors (FIG. 1) have been known to inhibit invasive migration of breast cancer cell lines and have been reported to be useful in blocking cancer metastasis.

Accordingly, the present inventors completed the present invention by confirming that a phospholipase inhibitor capable of inhibiting phospholipase D activity during the study of phospholipase D in rheumatoid arthritis shows efficacy in treating rheumatoid arthritis.

It is an object of the present invention to develop a material capable of preventing or treating rheumatoid arthritis, and to provide a composition for preventing or treating rheumatoid arthritis comprising the same as an active ingredient.

The present invention

It provides a composition for preventing or treating rheumatoid arthritis comprising a phospholipase D1 inhibitor as an active ingredient.

The present invention also

Provided is a health functional food for preventing or treating rheumatoid arthritis, comprising a phospholipase D1 inhibitor as an active ingredient.

Phospholipase D1 inhibitors of the invention inhibit articular cartilage destruction, inhibit bone destruction and produce inflammatory cytokines (TNF-α, IL-1β, IL-6 and IFN-γ, MCP-1 and IL-17) Since suppressing inflammation of the joint area by suppression shows an effect of remarkably improving the symptoms of rheumatoid arthritis, the composition of the present invention comprising a phospholipase D1 inhibitor having such characteristics as an active ingredient is useful for preventing or treating rheumatoid arthritis Can be used.

Figure 1 shows the chemical structural formula of the phospholipase D1 inhibitor of the present invention.
Figure 2 is an electrophoresis picture of mRNA expression of inflammation-related genes after treatment with interleukin-1 beta (IL-1β) and phospholipase D1 inhibitor in synovial cells (PLD1 inhibitor-phospholipase D1 inhibitor).
Figure 3 is an electrophoresis picture showing the protein expression of COX-2 and MMP-2 after treatment with interleukin-1 beta (IL-1β) and phospholipase D1 inhibitor in synovial cells (PLD1 inhibitor-phospholipase D1 inhibitor ).
Figure 4 is a graph showing the amount of inflammation-related cytokine production after treatment with interleukin-1 beta (IL-1β) and phospholipase D1 inhibitor (PLD1 inhibitor-phospholipase D1 inhibitor).
5 is a graph showing the degree of inhibition of the incidence of arthritis after administration of the phospholipase D1 inhibitor of the present invention to a collagen-induced arthritis mouse model (PLD1 inhibitor-phospholipase D1 inhibitor).
Figure 6 is a graph measuring the effect of treating paw edema after arthritis progression (index grade, scoring) over time after administration of the phospholipase D1 inhibitor of the present invention to the collagen-induced arthritis mouse model (PLD1 inhibitor- Phospholipase D1 inhibitors).
Figure 7 is a photograph showing the image of each mouse hind paw after administration of the phospholipase D1 inhibitor of the present invention to normal mice, collagen-induced arthritis mice and collagen-induced arthritis mice intraperitoneally (normal: normal mouse, vehicle: Collagen-induced arthritis mice, PLD1 inhibitors: mice administered with phospholipase D1 inhibitor).
8 is a micro-computed structure of each mouse knee and hind paw after administration of the phospholipase D1 inhibitor of the present invention to normal mice, collagen-induced arthritis mice and collagen-induced arthritis mice intraperitoneally. tomography scan) and three-dimensional reconstructed image photographs (normal: normal mice, vehicle: collagen-induced arthritis mice, PLD1 inhibitors: mice administered with phospholipase D1 inhibitors).
9 is a photograph of each mouse knee cross section stained with hematoclin / eozin after administration of the phospholipase D1 inhibitor of the present invention to normal mice, collagen-induced arthritis mice and collagen-induced arthritis mice intraperitoneally (FIG. normal: normal mice, vehicle: collagen-induced arthritis mice, PLD1 inhibitors: mice administered with phospholipase D1 inhibitor).
Figure 10 is a graph of histopathological analysis of the degree of inflammation of each mouse after administration of the phospholipase D1 inhibitor of the present invention to normal mice, collagen-induced arthritis mice and collagen-induced arthritis mice intraperitoneally (normal: normal Mice, vehicle: collagen-induced arthritis mice, PLD1 inhibitors: mice administered with phospholipase D1 inhibitor).
11 shows the inflammatory cytokines TNF-α, IL-1β, IL in each mouse serum after administration of the phospholipase D1 inhibitor of the present invention to normal mice, collagen-induced arthritis mice and collagen-induced arthritis mice intraperitoneally -6, IFN- [gamma], MCP-1 and IL-17 are the graphs showing the concentration (normal: normal mice, vehicle: collagen-induced arthritis mice, PLD1 inhibitor: mice administered with phospholipase D1 inhibitor).

Hereinafter, the present invention will be described in detail.

The present invention provides a composition for preventing or treating rheumatoid arthritis, comprising a phospholipase D1 inhibitor (PLD1 inhibitor) as an active ingredient.

The phospholipase D1 inhibitor of the present invention is not particularly limited as long as it is a substance capable of inhibiting phospholipase D1.

Specifically, the phospholipase D1 inhibitor which can be used as a composition for preventing or treating rheumatoid arthritis of the present invention is 1-butanol, (1R, 2R) -N-([S] -1- {4- [5-bromo -2-oxo-2,3-dihydro-1H-benzo (d) imidazole-1-yl] piperidin-1yl} propan-2yl) -2-phenylcyclopropanecarboxamide (VU0359595, C ₂₅ H ₂₉ BrN ₄ O ₂ ), N- (2- {4- [2-oxo-2,3-dihydro-1H-benzo (d) imidazole-1-yl] piperidin-1-yl} ethyl) -2-napthamide (VU0155056, C ₂₅ H ₂₆ N ₄ O ₂ ) and N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] -1-methylethyl]- 2-naphthalenecarboxamide (VU0155069, C ₂₆ H ₂₇ ClN ₄ O ₂ ) It may be one or more selected from the group consisting of.

In one embodiment of the invention the phospholipase D1 inhibitor is N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1 -piperidinyl] -1-methylethyl] -2-naphthalenecarboxamide.

N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] -1-methylethyl] -2-naphthalenecarboxamide Is a molecular formula C ₂₆ H ₂₇ ClN ₄ O ₂ , The molecular weight is 462.97. The chemical structure of the material is shown in FIG.

Phospholipase D1 inhibitor of the present invention has the effect of inhibiting inflammation of the joints, articular cartilage destruction and bone destruction, specifically tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1β) ), Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), MCP-1 (monocyte chemoattractant protein-1) and interleukin-17 (IL-17).

Therefore, the composition of the present invention comprising a phospholipase D1 inhibitor having such characteristics as an active ingredient can be usefully used for preventing or treating rheumatoid arthritis.

The composition for preventing or treating rheumatoid arthritis according to the present invention may be a pharmaceutical composition or a food composition.

A pharmaceutical composition comprising the phospholipase D1 inhibitor of the present invention as an active ingredient may be prepared using a pharmaceutically acceptable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant may include an excipient, a disintegrant, Sweetening agents, binders, coatings, expanding agents, lubricants, lubricants, or flavoring agents may be used.

The pharmaceutical composition may be formulated into a pharmaceutical composition containing at least one pharmaceutically acceptable carrier in addition to the above-described active ingredients for administration.

Formulation forms of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectable solutions. For example, for formulation into tablets or capsules, the active ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Also, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included as a mixture. Suitable binders include but are not limited to natural and synthetic gums such as starch, gelatin, glucose or beta-lactose, corn sweeteners, acacia, trackercance or sodium oleate, sodium stearate, magnesium stearate, sodium Benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Acceptable pharmaceutical carriers for compositions that are formulated into a liquid solution include sterile water and sterile water suitable for the living body such as saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, One or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.

The food composition comprising the phospholipase D1 inhibitor of the present invention as an active ingredient may be formulated in the same manner as the pharmaceutical composition, used as a functional food, or added to various foods. Foods to which the composition of the present invention may be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice creams, alcoholic beverages, vitamin complexes, and health supplements. There is this.

The present invention also provides a health functional food for preventing or treating rheumatoid arthritis, comprising a phospholipase D1 inhibitor as an active ingredient.

The phospholipase D1 inhibitor of the present invention is not particularly limited as long as it is a substance capable of inhibiting phospholipase D1.

The phospholipase D1 inhibitor is N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] -1- methylethyl] -2-naphthalenecarboxamide.

The functional food for preventing or treating rheumatoid arthritis may be beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, ice cream, alcoholic beverages, vitamin complexes or health supplements.

The present invention also provides the use of a composition comprising the phospholipase D1 inhibitor as an active ingredient for the prevention of rheumatoid arthritis, a medicament or the manufacture of food. The composition of the present invention comprising the phospholipase D1 inhibitor as an active ingredient can be used for the manufacture of a medicament or food for the prevention or treatment of diseases related to arthritis.

The present invention also provides a method of preventing or treating rheumatoid arthritis comprising administering to a mammal a therapeutically effective amount of a phospholipase D1 inhibitor.

As used herein, the term “mammal” refers to a mammal that is the subject of treatment, observation or experiment, preferably human.

As used herein, the term “therapeutically effective amount” means an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, doctor or other clinician, It is apparent to those skilled in the art that the therapeutically effective dosages and frequency of administrations for the active ingredients of the present invention will vary depending on the desired effect. The dosage of can be readily determined by one skilled in the art and includes the type of disease, the severity of the disease, the amount of active ingredients and other ingredients contained in the composition, the type of formulation, and the age, weight, general health, sex and diet of the patient. Can be adjusted according to a variety of factors including the time of administration, the route of administration and the rate of release of the composition, the duration of treatment, and the drug being used simultaneously. C. In the treatment method of the present invention, the adult phospholipase D1 inhibitor may be administered at a dose of 1 mg / kg to 500 mg / kg once or several times daily, preferably Preferably it is administered in a dose of 1mg / kg ~ 250mg / kg.

In the treatment method of the present invention, the composition comprising the phospholipase D1 inhibitor of the present invention as an active ingredient is an oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, intraocular or intradermal route. Can be administered in a conventional manner.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments and experimental examples described below in detail. However, the present invention is not limited to the embodiments and experimental examples disclosed below, but may be embodied in different forms, and only the exemplary embodiments and experimental examples are provided to make the present disclosure complete, and It is provided to fully alert those skilled in the art to the scope of the invention, and the invention is defined only by the scope of the claims.

[ Example ]

Example  1. Selection and treatment of experimental animal model

DBA1 / J male 20-25g mice were purchased from Central Experimental Animal Co., Ltd., and healthy animals showing adaptability through quarantine and purified breeding for 2 weeks were used for the experiment. This experiment was conducted in the SPF (specific pathogen free) animal breeding room of Yangsan Pusan National University Hospital with a breeding environment set at a temperature of 18-22 ° C, a relative humidity of 40-60%, and an illumination time of 12 hours (day and night cycles). All mice were freely fed solid animal feed and sterilized tap water (negative).

Example  2. Phospholipases for Mouse Intraperitoneal Administration D1  Inhibitor Injection Preparation

Injectable solution for treating arthritis according to the present invention was prepared by diluting a phospholipase D1 inhibitor using an electronic balance and then dissolving it in sterile PBS to dissolve in DMSO (dimethyl sulfoxide) and 10% DMSO. This injection was injected into the abdominal cavity of immunized collagen-induced arthritis mice at a total of 12 injections for 3 weeks at intervals of 5 mg / kg once every two days.

Example  3. Preparation of the Collagen-Induced Arthritis Mouse Model

To investigate the therapeutic effect of phospholipase D1 inhibitors, a collagen-induced arthritis mouse model test was performed.

The collagen-induced arthritis (CIA) mouse model is an arthritis model of the autoimmune disease family with characteristics similar to that of human rheumatoid arthritis.

Bovine type 2 collagen was homogeneously emulsified using a T-connector connected to a 3 ml syringe while cooling with Freund's adjuvant on ice. The emulsified collagen solution was injected intradermally into the tail base of 6-week-old DBA1 / J mice to administer an immunogen. On day 21 after primary immunization, bovine type 2 collagen was mixed with emulsified Freund's adjuvant and emulsified, followed by intradermal injection to the base of the tail to induce a second immunization (boosting) reaction. Symptoms began to appear gradually, and the clinical disease index of arthritis was determined. Visual observation of arthritis lesions was performed using the following score. 0: no swelling and redness, 1: slight redness and swelling of the ankle joint, 2: ankle joint redness and swelling distinct, 3: redness, including finger joints, severe swelling, 4: all areas of the joint Severe swelling throughout. Therefore, the best score for joint lesion was 4 per leg, and the best disease index was 16 for the left and right paws and hind paws per mouse.

Example  4. Comparison of Arthritis Index by Visual Observation

After the second immunization, the front and rear feet of the mouse were visually observed at two-day intervals to confirm whether arthritis due to inflammation occurred.

Experimental Example  1. Phospholipase D1  Inhibitor Proinflammatory Cytokines  Inhibitory effect

Fibroblast-like synoviocytes obtained during surgery in arthritis patients were collected and stimulated with IL-1β to stimulate proinflammatory cytokine and bone destruction enzyme matrix metalloproteinase (MMPs). ) To increase the amount of production. At this time, 5 and 10 μM of phospholipase D1 inhibitor were treated for each concentration, and cyclooxygenase 2 (COX-2), metalloproteinase-2 (MMP-2) and interleukin- Reverse transcription of proinflammatory mediators such as 6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), and MCP-1 (monocyte chemoattractant protein 1) It could be observed using the enzyme PCR method (see Fig. 2).

In the case of COX-2 and MMP-2, a decrease in transcription level was observed and the effect of the phospholipase D1 inhibitor at the translational level was examined by Western blot method. Inhibition of the protein expression level of MMP-2 was also observed (see Fig. 3).

In addition, the phospholipase D1 inhibitor in the present experiment was a concentration-dependent decrease in the production of VEGF (vascular endothelial growth factor), IL-6, IL-8, IL-15 and MCP-1 by ELISA method It could be confirmed (see FIG. 4).

Experimental Example  2. Experimental Effect of Arthritis Using Collagen-Induced Arthritis Mouse Model

Induction of the first immune response and three weeks after the induction of the second immune response, phospholipase D1 inhibitors were administered for three weeks at two-day intervals. After selecting 8 mice per group, the phospholipase D1 inhibitor was administered by intraperitoneal injection at 5 mg / kg in 10% DMSO. In the vehicle-treated group, only 10% DMSO was injected intraperitoneally. It then monitors the progression of arthritis and includes gross findings such as erythema and joint swelling at the joint site, histological findings such as hyperplasia of synovial cells at the joint site, cartilage and bone damage, and cytokine levels associated with inflammation. Molecular biological findings were examined to determine the extent of arthritis. The phospholipase D1 inhibitor did not show any toxicity signal and no lethality was observed.

When the incidence of arthritis was examined based on the degree of swelling, arthritis incidence was 100% in the vehicle-administered group, whereas the phospholipase D1 inhibitor-injected group was 30-40%. As a result, it was confirmed that the phospholipase D1 inhibitor of the present invention significantly reduced the incidence of arthritis (see FIG. 5).

When the degree of arthritis was intensified, the progression of arthritis at the ankle site was judged by gross findings such as swelling of the joint area. index). In addition, as a result of examining the arthritis progress index of the mouse, it was confirmed that the phospholipase D1 inhibitor-treated group significantly reduced the arthritis progression index compared to the vehicle-administered group (see FIGS. 6 and 7).

Experimental Example  3. Articular cartilage and bone analysis

In order to analyze cartilage and bone tissues of mice with arthritis three-dimensionally, the knee joints and hind feet of the mice were photographed with a micro-computed tomography scan and three-dimensional reconstruction with a software program. Knee joints and hind paws of vehicle-treated mice showed typical arthritis of cartilage and bone loss and deformity, and mice treated with phospholipase D1 inhibitor showed similar findings to normal mice. Was visually confirmed (see FIG. 8).

Experimental Example  4. Measurement of arthritis intensification

How to measure histopathological arthritis intensification

The most important of the pathologies of rheumatoid arthritis can be summarized as the hyperproliferation of joint synovial cells and the irreversible destruction of cartilage tissues.To determine the proliferation of these synovial cells and the progression of cartilage tissue damage, Most valid.

Knee tissues of normal mice, collagen-induced arthritis mice and mice administered with phospholipase D1 inhibitors to collagen-induced arthritis were isolated and fixed in 10% neutral buffered formalin (NBF) fixative solution, and using 10% EDTA solution. After decalcification, they were embedded in paraffin. Thereafter, 4 μm tissue sections were made and hematoxylin / eosin (hematoxylin / eosin) staining was performed (see FIG. 9).

Histological analysis was performed by separating knee joints of the vehicle-administered group and the phospholipase D1 inhibitor-administered group as a specific method of determining or measuring the indicators for measuring the degree of arthritis intensification. When trained researchers did not know which animals were given a vehicle or medication, the incidence and severity of arthritis was observed by hematoxylin / eosin staining, indicating synovial inflammation and bone erosion. erosion, cartilage damage, and leukocyte infiltration.

As a result, as shown in Figure 10, it was found that the phospholipase D1 inhibitor-treated group shows significantly lower values than the vehicle-administered group in all four evaluation criteria, through which the phospholipase D1 inhibitor of the present invention is synovial cells It can be inferred that it is effective in the treatment of arthritis through suppression of hyperproliferation and progression of cartilage damage.

Inflammation Using Molecular Biological Analysis Intensity  Measure

The concentration of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, INF-gamma, MCP-1 and IL-17) in mouse blood was measured using ELISA method.

As a result, as shown in FIG. 11, the phospholipase D1 inhibitor-administered group had a higher concentration of TNF-alpha, IL-1beta, IL-6, IFN-gamma, MCP-1 and IL-17 compared to the group administered with the vehicle. It was found to be significantly reduced (see FIG. 11).

In order to confirm the therapeutic effect of arthritis using phospholipase D1 inhibitor as a whole, the phospholipase D1 inhibitor of the present invention was tested in the collagen-induced arthritis mouse model to test the therapeutic effect on arthritis. Compared to the phospholipase D1 inhibitor-treated group, the incidence rate of arthritis was decreased, and the degree of swelling of the ankle joint was significantly decreased in the arthritic subjects. In addition, the histological findings of the knee joint region was significantly reduced damage to cartilage tissue compared to rheumatoid arthritis mice, it was confirmed that it is effective in suppressing and treating the development of arthritis of the present invention. The solution used for intraperitoneal administration was 10% DMSO mixed with PBS.

In particular, inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IFN-gamma), which are known to be closely involved in the progression of arthritis, when administered with the phospholipase D1 inhibitor of the present invention compared to rheumatoid arthritis mice Etc.) could be suppressed.

Claims (8)

N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl, a phospholipase D1 inhibitor ] -1-methylethyl] -2-naphthalenecarboxamide {N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl] -1-methylethyl] -2-naphthalenecarboxamide} A pharmaceutical composition for preventing or treating rheumatoid arthritis comprising as an active ingredient. delete The method of claim 1,
The phospholipase D1 inhibitor is a pharmaceutical composition for preventing or treating rheumatoid arthritis, characterized in that it inhibits articular cartilage destruction, inhibits bone destruction and inhibits inflammation of the joint area by inhibiting the production of inflammatory cytokines. The method of claim 3,
The inflammatory cytokine is TNF-α, IL-1β, IL-6 and IFN-γ, MCP-1 and IL-17 pharmaceutical composition for preventing or treating rheumatoid arthritis, characterized in that one selected from the group consisting of. delete N-[(1S) -2- [4- (5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) -1-piperidinyl, a phospholipase D1 inhibitor ] -1-methylethyl] -2-naphthalene carboxamide as an active ingredient for rheumatoid arthritis improvement food composition. delete The method according to claim 6,
The health functional food is rheumatoid, characterized in that one selected from the group consisting of beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gum, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements Food composition for improving arthritis.

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