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WO2012050370A2 - Composition pour prévenir ou traiter la polyarthrite rhumatoïde contenant un inhibiteur de sécrétase gamma en tant que composant actif - Google Patents

Composition pour prévenir ou traiter la polyarthrite rhumatoïde contenant un inhibiteur de sécrétase gamma en tant que composant actif Download PDF

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WO2012050370A2
WO2012050370A2 PCT/KR2011/007611 KR2011007611W WO2012050370A2 WO 2012050370 A2 WO2012050370 A2 WO 2012050370A2 KR 2011007611 W KR2011007611 W KR 2011007611W WO 2012050370 A2 WO2012050370 A2 WO 2012050370A2
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formula
gamma
secretase inhibitor
rheumatoid arthritis
present
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PCT/KR2011/007611
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Korean (ko)
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WO2012050370A3 (fr
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조동규
박종성
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성균관대학교산학협력단
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Priority claimed from KR1020110100981A external-priority patent/KR101330184B1/ko
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Publication of WO2012050370A3 publication Critical patent/WO2012050370A3/fr

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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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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

Definitions

  • the present invention relates to a composition for preventing or treating rheumatoid arthritis, which contains a gamma-secretase inhibitor as an active ingredient.
  • Rheumatoid arthritis is an autoimmune disease, a chronic inflammatory disease associated with chronic inflammation of the joints. Often, inflammation spreads to tissues and other organs around the joints. In general, rheumatoid arthritis is a progressive disease that can lead to joint destruction and dysfunction, and joint inflammation associated with rheumatoid arthritis causes swelling, pain, stiffness and redness of the joint. Joint inflammation associated with rheumatoid arthritis can also occur in the tissues around the joint (tendons, ligaments, muscles). In some patients with rheumatoid arthritis, chronic inflammation destroys cartilage, bones and ligaments, causing joint deformation. Damage to joints can occur early in the disease and can be progressive. Progressive damage of the joints does not necessarily correlate with the degree of pain, stiffness or swelling in the joint.
  • gamma-secretase is a protein mainly studied in the treatment of Alzheimer's dementia and plays an important role in producing amyloid beta peptides, which are known to be the main cause of Alzheimer's dementia.
  • Gamma-secretase is a co-complex proteolytic activator consisting of four proteins, for example presenilin, nicastrin, pen-2, aph-1. Presenilins represent a new group of anomalous aspartyl proteases that are essential for the activity of gamma-secretase and cleave in the trans membranes of these substrates to become polytopic membrane proteins themselves.
  • Nicastin is a protein of relatively large molecular weight and is a structural unit of gamma-secretase present in the cell membrane. When present, the nicastrin acts as a receptor while the nicotine is directed out of the cell. It also forms bonds with some cells present in the cell membrane, including amyloid precursor protein (APP). Once the bond is formed, the amyloid precursor protein is moved to the active site of gamma-secretase, where the protein splits into two sites where the amyloid-beta exits the cell and the other site remains inside the cell. Amyloid-beta secreted out of the cells accumulates in the brain, creating plaques, which is a hallmark of Alzheimer's disease. The exact function of pen-2 and aph-1 is unknown (Wolfe MS, Biochemistry, 2006, 45, 7931-9).
  • Such gamma-secretase not only degrades amyloid beta precursor protein but also has various substrates such as Notch, CD44, N-cadherin, and IGF1-R.
  • Notch has signaling mechanisms associated with inflammatory responses. Notch signaling regulates the differentiation, proliferation, survival and development of various cells. There are four notch receptors in mammalian cells ranging from Notch 1 to 4, and jagged-1,2 and delta-like-1,3. 4) It has a total of 5 ligands.
  • Notch receptors When Notch receptors are activated after binding to ligands, two steps of proteolysis occur by the metalloproteases ADAM and gamma-secretase, which produce the notch intracelluar domain (NICD), which enters the nucleus and acts as a transcriptional regulator. do.
  • ADAM metalloproteases
  • gamma-secretase gamma-secretase
  • Notch signaling in mammals is involved in several stages in the development of T cells and B cells, and is also involved in the activation of T cells, the function of regulatory T cells and the differentiation of helper T cells.
  • Notch signaling has also been reported to regulate differentiation and survival of dendritic cells (DCs) and to regulate the production of toll-like receptors (TLRs), which are abundantly produced in the joints of patients with rheumatoid arthritis (Amsen).
  • DCs dendritic cells
  • TLRs toll-like receptors
  • Notch signaling is highly expressed in joint tissues of patients with rheumatoid arthritis and is known to increase the release of cytokines produced by rheumatoid arthritis (Nakazawa, et al., Arthritis and Rheumatism, 2001, 44, 1545-54). Ando, et al., Oncogene, 2003, 22, 7796-7803, Yabe, et al., J. Orthop. Sci., 2005, 10, 589-94).
  • the present inventors are studying the anti-inflammatory effects of gamma-secretase inhibitors on joint inflammation associated with rheumatoid arthritis, and the gamma-secretase inhibitors reduce the degree of arthritis induction in a concentration-dependent manner, The present invention was confirmed to reduce influx, decrease the amount of cytokines and chemokines, and reduce the amount of expression of the notch intracelluar domain (NICD), thus completing the present invention.
  • NICD notch intracelluar domain
  • the present invention is to provide a composition for the prevention or treatment of rheumatoid arthritis containing a gamma-secretase inhibitor as an active ingredient.
  • the present invention provides a composition for the prevention or treatment of rheumatoid arthritis containing a gamma-secretase inhibitor as an active ingredient.
  • the composition includes a pharmaceutical composition and a food composition.
  • Gamma-secretase inhibitors are DAPT, L-685,458, RO4929097, DBZ, Z-YIL-CHO, DAPM, compound E, CW, begacestat (GSI-953), semagacestat (LY450139), BMS 299897 and MRK One or more selected from the group consisting of 560, but is not limited thereto.
  • the DAPT N-[(3,5-difluorophenyl) acetyl] -L-alanyl-2-phenyl] glycine-1,1-dimethylethyl ester
  • the DAPT is a white solid, the molecular formula C 23 H 26 F 2 N 2 O 4 , Molecular weight 432.46, CAS No. 208255-80-5.
  • L-685,458 ((5S)-(tert-butoxycarbonylamino) -6-phenyl- (4R) -hydroxy- (2R) -benzylhexanoyl) -L-leucy-L-phenylalaninamide) is represented by the molecular formula C 39 H 52 N 4 O 6 , Molecular weight 672.85, CAS No. 292632-98-5.
  • the RO4929097 is represented by the following Chemical Formula 1, a molecular formula C 22 H 20 F 5 N 3 O 3 , molecular weight 469.4, CAS No. 847925-91-1.
  • DBZ (dibenzazepine; (S, S) -2- [2- (3,5-difluorophenyl) acetylamino] -N- (5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b, d ] azepin-7-yl) propionamide) is a white solid, formula C 26 H 23 F 2 N 3 O 3 , molecular weight 463.4, CAS No. 209984-56-5.
  • the Z-YIL-CHO is represented by the following Chemical Formula 2, and is a white, lyophilized solid, having a molecular formula of C 29 H 39 N 3 O 6 , a molecular weight of 525.7.
  • the DAPM N- [N-3,5-difluorophenacetyl] -L-alanyl-S-phenylglycine methyl ester
  • the DAPM has the molecular formula C 20 H 20 F 2 N 2 O 4 , molecular weight 390.4.
  • Compound E ((S, S) -2- [2- (3,5-difluorophenyl) -acetylamino] -N- (1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepin-3-yl) -propionamide) is an off-white powder, molecular formula C 27 H 24 F 2 N 4 O 3 , having a molecular weight of 490.5.
  • the CW (3,5-bis (4-nitrophenoxy) benzoic acid) is a molecular formula C 19 H 12 N 2 O 8 , molecular weight 396.31, CAS No. 173550-33-9.
  • the begacestat (GSI-953) is represented by the following Chemical Formula 3, the molecular formula C 9 H 8 ClF 6 NO 3 S 2 , molecular weight 391.74, CAS No. 769169-27-9.
  • the semagacestat (LY450139) is represented by the following formula 4, the molecular formula C 19 H 27 N 3 O 4 , molecular weight is 361.434.
  • the BMS 299897 is represented by the following Chemical Formula 5, the molecular formula C 24 H 21 ClF 3 NO 4 S, molecular weight 511.94, CAS No. 290315-45-6.
  • the MRK 560 (N- [cis-4-[(4-chlorophenyl) sulfonyl] -4- (2,5-difluorophenyl) cyclohexyl] -1,1,1-trifluoromethanesulfonamide) is represented by the following Chemical Formula 6, formula C 19 H 17 ClF 5 NO 4 S 2 , molecular weight 517.92, CAS No. 677772-84-8.
  • Gamma-secretase inhibitors reduce the degree of arthritis induction, reduce the influx of inflammatory cells into the knee joint, reduce the amount of cytokines and chemokines, and express the notch intracelluar domain (NICD). Reduce the amount.
  • the gamma-secretase inhibitor according to the present invention has an excellent inhibitory effect on the production of NICD, which plays an important role in notch signal transduction, which triggers an inflammatory response by regulating the activation, differentiation and proliferation of immune cells. It can be used as a medicine and health functional food useful for the prevention or treatment of arthritis.
  • composition of the present invention may contain one or more known active ingredients having a prophylactic or therapeutic effect of rheumatoid arthritis together with a gamma-secretase inhibitor.
  • composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.
  • Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.
  • composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
  • the daily dose of the gamma-secretase inhibitor is about 1 to 500 mg / kg, preferably about 150 to 250 mg / kg, preferably administered once to several times a day.
  • composition of the present invention can be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers for the prevention or treatment of rheumatoid arthritis.
  • the composition of the present invention may be added to a dietary supplement for the purpose of preventing rheumatoid arthritis.
  • the gamma-secretase inhibitor of the present invention can be added as it is or used with other foods or food ingredients, and can be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment).
  • the gamma-secretase inhibitors of the invention are added in amounts of up to 15% by weight, preferably up to 10% by weight, based on the raw materials in the manufacture of food or beverages.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes, and includes all of the dietary supplements in the conventional sense.
  • the health beverage composition of the present invention may contain various flavors or natural carbohydrates, etc. as additional components, as in the general beverage.
  • Natural carbohydrates described above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • sweetening agent natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used.
  • the proportion of the natural carbohydrate is generally about 0.01 to 0.20 g, preferably about 0.04 to 0.10 g per 100 mL of the composition of the present invention.
  • the composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, And a carbonation agent used for the carbonated beverage.
  • the composition of the present invention may contain a pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not critical but is usually selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the gamma-secretase inhibitor according to the present invention reduces the degree of arthritis induction, decreases the influx of inflammatory cells into the knee joint, reduces the amount of cytokines and chemokines, and activates, differentiates and proliferates immune cells. It is effective to reduce the amount of expression of the notch intracelluar domain (NICD), which plays an important role in notch signal transduction, which causes an inflammatory response.
  • notch intracelluar domain (NICD)
  • DAPT gamma-secretase inhibitor
  • Figure 2 is a diagram showing the quantification of the degree of arthritis of the gamma-secretase inhibitor (DAPT) of the present invention.
  • DAPT gamma-secretase inhibitor
  • Figure 3 is a graph showing the degree of arthritis induction of the gamma-secretase inhibitor (DAPT) of the present invention in clinical scores.
  • DAPT gamma-secretase inhibitor
  • Figure 4 is a microscopic view of histological inflammation in the knee joint of the rheumatoid arthritis animal model treated with gamma-secretase inhibitor (DAPT) of the present invention.
  • DAPT gamma-secretase inhibitor
  • FIG. 5 shows cytokines (IL-6, IL-12, IL-17, TNF-a, INF- ⁇ ) in serum of a rheumatoid arthritis animal model treated with a gamma-secretase inhibitor (DAPT) of the present invention. This is a measure of the amount of chemokine (MCP-1) released.
  • cytokines IL-6, IL-12, IL-17, TNF-a, INF- ⁇
  • Figure 6 is a diagram confirming the degree of NICD expression in the joints of the rheumatoid arthritis animal model treated with the gamma-secretase inhibitor (DAPT) of the present invention.
  • DAPT gamma-secretase inhibitor
  • Figure 7 is a graph showing the degree of arthritis induction of the gamma-secretase inhibitors (L-685,458, RO4929097, DBZ) of the present invention.
  • FIG. 8 is a microscopic view of histological inflammation in the knee joint of a rheumatoid arthritis animal model treated with a gamma-secretase inhibitor of the present invention (L-685,458, RO4929097, DBZ).
  • a gamma-secretase inhibitor of the present invention L-685,458, RO4929097, DBZ.
  • DAPT gamma-secretase inhibitor
  • a collagen induced arthritis model was constructed.
  • an 8-week-old C57BL / 6J mouse was purchased and adjusted to the environment by supplying enough food and water for a month in a constant temperature / humidity animal breeding room that maintains a temperature of 22 ° C and a dark / light cycle of 12 hours. It was used for later experiments.
  • Rheumatoid arthritis animal models were constructed of 12-week-old C57BL / 6J mice in the same manner as the nature protocol.
  • DAPT gamma-secretase inhibitor
  • NIRF near-infrared fluorescence
  • HGC hydrophobically modified glycol chitosan
  • FIGS. 1 and 2 The degree of arthritis induction and the result of quantification of DAPT, a gamma-secretase inhibitor of the present invention, are shown in FIGS. 1 and 2, respectively, and the result of measuring the degree of arthritis in clinical scores is shown in FIG. 3.
  • DAPT a gamma-secretase inhibitor
  • DAPT gamma-secretase inhibitor
  • the knee joint was extracted after intraperitoneally administering DAPT (10 mg / kg, 20 mg / kg) for 4 weeks to the animal model of rheumatoid arthritis prepared in Example 1.
  • the extracted knee joint was fixed in 10% NBF (neutral buffered formalin).
  • the fixed knee joint was decalcified using decalcifying solution lite (Sigma) to decalcify bone and make paraffin blocks.
  • the prepared paraffin block joint tissue was made into 5 ⁇ m sections, stained with hematoxylin and eosin, and observed under a microscope.
  • influx of inflammatory cells occurred due to an inflammatory response of the knee joint in the knee joint tissue section of the rheumatoid arthritis animal model, but influx of inflammatory cells was decreased in the DAPT-treated group.
  • DAPT gamma-secretase inhibitor
  • DAPT DAPT
  • IL-6, IL-12, IL-17, TNF-a, INF- ⁇ cytokine
  • chemokine using Mouse Cytokine Panel 1-8 Plex (Millipore, MPXMCYTO-70K-08, USA) The amount of release of (MCP-1) was measured.
  • the serum of the rheumatoid arthritis animal model was released a large amount of cytokines and chemokines, the amount of cytokines and chemokines was reduced in the DAPT group.
  • DAPT gamma-secretase inhibitor
  • Notch 1 was increased in the joints of the rheumatoid arthritis animal model, but the expression level of NICD was decreased in the DAPT-administered group.
  • DAPT gamma-secretase inhibitors (L-685,458, RO4929097, DBZ) of the present invention
  • L-685,458 Tocris bioscience, Cat.No: 2627, UK
  • RO4929097 Selleck chemical, S1575 USA
  • DBZ Calbiochem, Cat.No: 565789, Germary
  • the influx of inflammatory cells occurred due to the inflammatory response of the knee joint in the knee joint tissue fragment of the rheumatoid arthritis animal model, but the influx of inflammatory cells in the group administered with L-685,458, RO4929097, and DBZ. This has been reduced.
  • the amount of cytokines (IL-6, IL-12, IL-17, TNF-a, INF- ⁇ ) was released in the serum of the rheumatoid arthritis animal model, L-685,458, RO4929097 , The amount of cytokines decreased in the group receiving DBZ.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • Injectables were prepared by mixing the above ingredients per ampoule (2 mL) according to the conventional method for preparing injectables.
  • Foods containing the gamma-secretase inhibitor of the present invention were prepared as follows.
  • a health promotion cooking seasoning was prepared with a gamma-secretase inhibitor of 20-95 wt%.
  • Gamma-secretase inhibitor 0.5-5.0% by weight was added to the flour and using this mixture to prepare bread, cakes, cookies, crackers and noodles to produce health foods.
  • gamma-secretase inhibitor 0.1-5.0% by weight of gamma-secretase inhibitor was added to the soup and gravy to prepare health promoting meat products, soups of noodles and gravy.
  • gamma-secretase inhibitor 5-10% by weight of gamma-secretase inhibitor was added to the milk, and the milk was used to prepare various dairy products such as butter and ice cream.
  • Gamma-secretase inhibitor (2.5% solids, 97.16%), jujube extract (65 brix, 2.67%), overweight extract (70% solids, 0.12%), vitamin C (0.02%), calcium pantonthenate (0.02% ), Licorice extract (65% solids, 0.01% solids) was homogeneously blended and instant sterilized and then packaged in a small packaging container such as glass bottles and plastic bottles to prepare a healthy beverage.
  • gamma-secretase inhibitor 0.5 g was added to 1,000 mL of tomato or carrot juice to prepare vegetable juice for health promotion.
  • gamma-secretase inhibitor 0.1 g was added to 1,000 mL of apple or grape juice to prepare fruit juice for health promotion.
  • NICD Notch Intracelluar Domain
  • a composition comprising a gamma-secretase inhibitor as an active ingredient can be usefully used for the treatment and prevention of representative rheumatoid arthritis of autoimmune diseases, and health functional food can be widely used for the prevention of rheumatoid arthritis. It is expected to be.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter la polyarthrite rhumatoïde contenant un inhibiteur de sécrétase gamma en tant que composant actif. L'inhibiteur de sécrétase gamma selon la présente invention réduit le degré d'induction d'arthrite et réduit l'afflux de cellules inflammatoires dans l'articulation du genou, de façon dose-dépendante, et réduit également la quantité de cytokines et de chimiokines, et réduit la quantité d'expression de NICD (domaine Notch intracellulaire). Par conséquent, l'inhibiteur de sécrétase gamma selon la présente invention peut être utilisé en tant que produit médicinal et aliment de santé fonctionnel qui est utile dans la prévention ou le traitement de la polyarthrite rhumatoïde, étant donné qu'il régule l'activation, la différenciation et la croissance de cellules immunitaires et a donc un effet remarquable dans la suppression de la production de NICD qui joue un rôle très important dans la transmission de signal Notch de telle manière que des réactions inflammatoires surviennent.
PCT/KR2011/007611 2010-10-15 2011-10-13 Composition pour prévenir ou traiter la polyarthrite rhumatoïde contenant un inhibiteur de sécrétase gamma en tant que composant actif WO2012050370A2 (fr)

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KR10-2010-0100716 2010-10-15
KR20100100716 2010-10-15
KR1020110100981A KR101330184B1 (ko) 2010-10-15 2011-10-05 감마-세크레타제 저해제를 유효성분으로 함유하는 류마티스성 관절염의 예방 또는 치료용 조성물
KR10-2011-0100981 2011-10-05

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CN115364282A (zh) * 2022-09-05 2022-11-22 东莞市人民医院 双功能血管支架及其制备方法

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EA009940B1 (ru) * 2003-09-09 2008-04-28 Ф. Хоффманн-Ля Рош Аг ПРОИЗВОДНЫЕ МАЛОНАМИДА, БЛОКИРУЮЩИЕ АКТИВНОСТЬ γ-СЕКРЕТАЗЫ
AU2009203776A1 (en) * 2008-01-11 2009-07-16 F. Hoffmann-La Roche Ag Use of a gamma-secretase inhibitor for treating cancer

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