WO2003011276A1 - Inhibiteur nf$g(k)b - Google Patents

Inhibiteur nf$g(k)b Download PDF

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Publication number
WO2003011276A1
WO2003011276A1 PCT/JP2002/007400 JP0207400W WO03011276A1 WO 2003011276 A1 WO2003011276 A1 WO 2003011276A1 JP 0207400 W JP0207400 W JP 0207400W WO 03011276 A1 WO03011276 A1 WO 03011276A1
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WIPO (PCT)
Prior art keywords
cape
skin
disease
cardiac hypertrophy
acid
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PCT/JP2002/007400
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English (en)
Japanese (ja)
Inventor
Toshio Nakaki
Keiichi Hishikawa
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M's Science Corporation
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Priority to JP2003516506A priority Critical patent/JPWO2003011276A1/ja
Publication of WO2003011276A1 publication Critical patent/WO2003011276A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention is characterized by containing caffeine phenethyl esters, and is characterized by hypertrophic disease, hyperlipidemia, glaucoma, bronchial asthma, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Cr
  • the present invention relates to a prophylactic / therapeutic agent for diseases such as ohn disease) or skin diseases.
  • Cardiac hypertrophy is a compensatory mechanism for maintaining cardiac output against hypertension.
  • coronary blood flow regulation abnormalities such as an increase in coronary vascular resistance, a decrease in coronary blood flow reserve capacity, and an increase in the lower limit of automatic coronary blood flow autoregulation occur, and the above-mentioned compensation mechanism is limited.
  • cardiac contractility gradually decreases and may lead to cardiovascular diseases such as ischemic heart disease or heart failure (Marcus ML et al., Circulation, 75 (Suppl. 1), 119-125 (1987)). Furthermore, there is a danger that sustained overload will lead to a decline in cardiac function, such as a gradual decrease in myocardial contractility, leading to ventricular arrhythmias, cardiac ischemia, coronary artery disease, and congestive heart failure. Yes, and sometimes sudden death.
  • cardiovascular diseases such as ischemic heart disease or heart failure (Marcus ML et al., Circulation, 75 (Suppl. 1), 119-125 (1987)).
  • sustained overload will lead to a decline in cardiac function, such as a gradual decrease in myocardial contractility, leading to ventricular arrhythmias, cardiac ischemia, coronary artery disease, and congestive heart failure. Yes, and sometimes sudden death.
  • lipids in the blood are increased for a long time, causing lipids to deposit on the inner walls of blood vessels and hardening of the arterial walls.
  • lipids cholesterol and triglycerides
  • hardening of the arterial wall life-threatening complications such as angina and myocardial infarction in the heart and cerebral infarction in the brain are liable to occur.
  • HMG—C0A reductase inhibitors which inhibit the function of the cholesterol synthesis pathway in the body, which is the mainstay of pharmaceutical products, include striated muscle melting action and liver dysfunction. There are side effects and rebounds.
  • drawbacks such as poor quality and discomfort. There is. Long-term dietary restrictions, which deprive the pleasure of eating and have to endure, are also unfavorable.
  • an object of the present invention is to provide a composition that suppresses cardiac hypertrophy itself and is effective in preventing or treating complications associated with human hyperlipidemia in view of the above problems.
  • the present inventors have conducted various studies in order to solve the above-mentioned problems, and as a result, it has been found that the use of phenethyl caffeate as an active ingredient is effective in treating the above-mentioned diseases. And found that the present invention was completed.
  • FIG. 1 is a diagram comparing the survival rates of SHRS P / izm rats fed CAPE and controls. Open circles indicate controls, and black filled triangles indicate SHRS P / izm rats fed CAP E.
  • Figure 2 shows the total weight of SHRS P / izm rats fed CAPE and controls. It is the figure which compared the weight ratio of the heart with respect to.
  • FIG. 3 is a diagram comparing the weight ratio of the left ventricle to the total body weight of SHRSPZizm rats fed CAPE and control.
  • FIG. 4 is a diagram comparing the weight ratio of the aorta to the total body weight of SHRS P / izm rats fed CAPE and control.
  • FIG. 1 is a diagram comparing the survival rates of SHRS P / izm rats fed CAPE and controls. Open circles indicate controls, and black filled triangles indicate SHRS P / izm rats fed CAP E.
  • Figure 2 shows the total weight of SHRS P / iz
  • FIG. 5 is a graph comparing the expression rates of NF ⁇ -related genes in the left ventricle of SHRS PZizm rats fed CAPE and control. Other genes are genes that are not related to NF ⁇ .
  • FIG. 6 is a diagram comparing the expression rates of NF ⁇ -related genes in SHRSP / izm rats fed CAPE and control aorta. Other genes are genes that are not related to NF ⁇ .
  • FIG. 7 is a diagram comparing the cholesterol level and the triglyceride level of the Apo-E knockout mouse given CAPE and the control. In the bar graph in the figure, the lightly shaded area indicates the control, and the darkly shaded area indicates the Apo-E knockout mouse to which CAPE was given.
  • TC indicates total cholesterol
  • TG indicates triglyceride
  • HDL-C indicates high-density lipoprotein cholesterol
  • LDL-C indicates low-density lipoprotein cholesterol.
  • FIG. 8 is a graph comparing fat deposition in the aorta of the Apo-E knockout mouse fed CAPE and the control mouth.
  • A shows a control
  • (b) shows an Apo-E knockout mouse given CAPE.
  • FIG. 9 is a diagram comparing the expression rates of NF ⁇ B-related genes in Apo-E knockout mice fed CAPE and control aorta. Other genes indicate genes that are not related to NF ⁇ .
  • caffeic acid phenethyl esters are not particularly limited, and known substances may be used.
  • CAPE and its structural analogs may be collected from natural sources or chemically synthesized, and can be obtained according to known methods, as long as they exhibit the desired effect.
  • the source and origin are not particularly limited as long as they do not contradict the purpose of the present invention.
  • Natural sources include, for example, propolis and leaf stems of Asteraceae plants, such as potato mogi.
  • Examples of the structural analog of CAPE include (a) a structural analog in which a benzene ring group is substituted, that is, a structural analog in which the substituent of a benzene ring derived from caffeic acid is changed or Z is added, and more specifically. In some cases, the substituent of the benzene ring derived from caffeic acid is replaced with a different substituent, or the configuration of the substituent of the benzene ring is changed. Structural analogs in which the substituent is changed, the position of the substituent on the benzene ring is changed, and a substituent is further added to the benzene ring. In addition, (b) a structural analog in which the length of an alkyl spacer is changed, (c) a bicyclic structural analog, or (d) a saturated amide structural analog is also exemplified.
  • Structural analogs substituted with a benzene ring group include, for example, positional isomers of 3,4-dihydroxy type of CAPE, structural analogs substituted with 2,5-hydroxy type,
  • Examples include structural analogs in which the hydroxyl group of CAPE is substituted with an acetyl group, and 2,3,4-trihydroxy derivatives having a hydroxyl group added.
  • Examples of the structural analog in which the length of the alkyl spacer is changed include a structural analog in which the length of the alkyl spacer is changed by changing the phenethyl side chain.
  • Bicyclic structural analogs include, for example, bicyclic 5,6-hydroxy analogs, bicyclic 6,7-hydroxy analogs, or bicyclic 3,4-hydroxy analogs.
  • Examples of the saturated amide structural analogue include those obtained by replacing a carbonyl group of CAPE with an amide group.
  • CAPE used in the present invention has the following formula (A):
  • the active ingredient of the agent for preventing or treating diseases according to the present invention is preferably CAPE, 2 5 _Hydroxyphenethyl ester, 2,5-dihydroxycinamic acid phenethyl ester, bicyclic 5,6-hydroxy analogues are used, more preferably bicyclic 5,6-dihydroxy analogues. Used.
  • Examples of the bicyclic 5,6-dihydroxy type analog include the analog represented by the above formula (6).
  • Any of the above CAPE structural analogs can be easily produced by a known method or a method known per se. For example, the above structural analog is Grunberger, D., Banner] 'ee, R., Esinger, K., 01tz, K., Efros, ⁇ .
  • CAPEs according to the present invention inhibit the transcription of DNA having an NF / cB recognition sequence by specifically inhibiting the transcription factor NF ⁇ bound to DNA. Therefore, CAPEs can effectively inhibit the expression of a protein corresponding to the gene if it has a NF ⁇ recognition sequence.
  • Genes having NF ⁇ B recognition sequences include, for example, interleukin (hereinafter abbreviated as IL) -1, major necrosis factor (hereinafter abbreviated as TNF), IL-12, IL-16, IL — 8, granulocyte colony stimulating factor (G-CSF), interferon) 3 (INF_
  • IL interleukin
  • TNF major necrosis factor
  • IL-12 major necrosis factor
  • IL-16 IL-12
  • IL-16 granulocyte colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • genes involved in immune and inflammatory reactions including genes for adhesion molecules.
  • A Receptor gonists of inflammatory cytokines such as IL-1 receptor antagonist (IL-1RA) and other major histocompatibility complex (MHC) class I, MHC Class II,) 32 macroglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4 protein genes, and (b) one of the oncogenes, the C-myc gene,
  • C Human immunodeficiency virus (HIV) ⁇ human T-cell leukemia virus (HTLV-I), cytomega Genes such as rovirus (CMV) and adenovirus. It is thought that the transcription of viral genes is activated by NF ⁇ B in the host cell, which promotes virus growth and infection.Therefore, CAPEs suppress viral expression by suppressing the expression of these genes. It can prevent and treat diseases related to these, such as illness.
  • IL-1 receptor antagonist IL-1 receptor antagonist
  • MHC major histocompatibility complex
  • the CAPEs according to the present invention include, for example, cardiac hypertrophy, hyperlipidemia and complications associated with hyperlipidemia, atherosclerosis, Alzheimer's disease, glaucoma, systemic lupus erythematosus, systemic scleroderma, Behcet Various autoimmune diseases including diseases, periarteritis nodosa, active chronic hepatitis, glomerulonephritis, etc .; rheumatoid arthritis, osteoarthritis, gout, psoriasis, atopic dermatitis, bronchial asthma, granuloma Inflammatory diseases such as various encephalitis, intractable diseases, endotoxin shock, sepsis, inflammatory bowel disease, diabetes, acute myeloblastic leukemia, pneumonia, heart transplant, brain Myelitis, anorexia, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), acute hepatitis, chronic hepati
  • the agent according to the present invention can be obtained by formulating an amount in which the CAPEs according to the present invention exert an effect, if desired, in combination with an appropriate pharmaceutical carrier or other auxiliary agents according to a conventional method.
  • the term “effective amount” as used herein refers to an amount that exhibits a pharmacological activity that is self-sustaining. Preferably, the amount is such that there are few side effects and the desired pharmacological activity is exhibited.
  • the CAPEs according to the present invention are administered as oral preparations or parenteral preparations in the form of solid preparations, ointments, liquid preparations and the like.
  • the oral preparation is not particularly limited, and various acceptable It may be administered orally as a possible dosage form, for example, a tablet, a coated tablet, a powder, a granule, a capsule, a liquid such as a suspension or a poultice.
  • the parenteral preparation is not particularly limited, and may be parenterally administered, for example, as a suppository, an external preparation, a drip, a transdermal absorbent, an injection such as an intravenous injection, and the like.
  • Pharmaceutical carriers generally used with the active ingredient according to the present invention may be solid or liquid, and are usually selected in consideration of the administration route.
  • the solid carrier include lactose, sucrose, gelatin, and cold.
  • the liquid carrier include water, syrup, peanut oil, and olive oil.
  • a suitable carrier known in the art may be used.
  • excipients include, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, and the like
  • binders include, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, and Arabic Rubber, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin, pectin and the like.
  • Disintegrators include, for example, starch, hydroxypropyl starch, corn arsenide and the like.
  • Lubricants include, for example, magnesium stearate, talc, polyethylene dalicol, silica, hydrogenated vegetable oil and the like.
  • Colorants are permitted to be added to pharmaceuticals, and flavoring agents include, for example, cocoa powder, fragrance acid, heart oil, dragon brain, cinnamon powder, and the like. Tablets or granules may be appropriately coated with sugar coating, gelatin coating, or the like, if desired. Further, a preservative, an antioxidant and the like can be added as required.
  • a pH adjuster, a buffer, a stabilizer, a solubilizer, etc. may be added to the main drug as desired, and further desired Lyophilized, etc. to obtain injections for subcutaneous, intramuscular, and intravenous injections and infusions in the usual manner.
  • the dosage of the drug according to the present invention varies depending on, for example, the administration method, individual differences between patients to be administered, the type of disease, the condition of the patient at the time of administration, and cannot be unconditionally determined.
  • about 0.001 to 20 mg / kg of CAPEs can be administered once or several times a day.
  • CAPEs according to the present invention are also effective for thickening, pigmentation, skin exfoliation, rough skin, disturbed texture, denaturation and destruction of dermis components, etc. in the skin.
  • the agent according to the present invention can be in the same form as a normal external preparation for topical application, and can be prepared according to a conventional method.
  • Examples of the form of the external preparation for the skin include a lotion, a semi-liquid emulsion, a cream type having a flexible consistency, a gel type emulsion, and a foam.
  • the use amount of CAPEs is preferably about 0.00000001 to 10% by weight in the external preparation for skin.
  • the external preparation for skin of the present invention includes additives incorporated in ordinary external preparations for skin, such as emulsifiers, solvents, water-absorbing gelling agents, lipophilic gelling agents, water-absorbing active ingredients, and lipophilic. Active ingredients, preservatives, antioxidants, fragrances, fillers and the like can be added. These amounts may be those usually used in external preparations, and may be, for example, about 0.01 to 20% by weight in the skin external preparation.
  • Examples of the emulsifier include glycerol monostearate, polysorbate 60, and a mixture of PEG-6 / PEG-32 / glycolsterate (Gattefosse: Te fose).
  • Examples of the solvent include lower alcohols, and ethanol and isopanol are particularly preferred.
  • Examples of the water-absorbing gelling agent include carboxylic acid polymer, acrylic polymer, polyacrylamide, polysaccharide, and natural rubber.
  • Examples of lipophilic gelling agents include modified clay, metal salts of fatty acids, hydrophobic silica And the like.
  • water-absorptive active ingredient examples include proteins, protein hydrolysates, amino acids, polyalcohols, urea, allantoin, saccharides and derivatives thereof, vitamins, and hydroxy acids.
  • lipophilic active ingredient examples include retinol and its derivatives, tocopher and its derivatives, essential fatty acids, ceramides, essential oils, salicylic acid and its derivatives, and the like.
  • Such agents include, for example, anti-pacteria, anti-bacterial, anti-inflammatory, anti-pruritic, anti-viral, keratolytic, anti-free radical, anti-oxidant, anti-sebum, anti-acne, anti-acne One or more selected from humectants and humectants.
  • the antibacterial agent include clindamycin phosphate, erythromycin, and tetracycline antibiotics.
  • Examples of the antibacterial agent include imidazole-type compounds such as econazole, ketoconazole, miconazole and salts thereof, boren compounds such as amphotericin B, and alisamines such as terbinafine and octopirox.
  • anti-inflammatory agents examples include steroids such as hydrocotisone and benzomethasone, ibuprofen and its salts, acetylsalicylic acid, acetoaminophen, glycyrrhizic acid and the like.
  • Antipruritic agents include, for example, tenaldine, trimeprazine, cyproheppudin and the like.
  • antiviral agent examples include acyclovir.
  • Examples of the keratolytic agent include ⁇ -hydroxycarboxylic acid and its salt,) 3-hydroxycarboxylic acid and its salt, / 3-ketocarboxylic acid and its salt, amide, and ester, for example, glycolic acid, lactic acid, salicylic acid, Examples include hydroxy acids such as citric acid, fruit acids, and ⁇ -tactanyul 5-salicylic acid.
  • Antifree radical agents include, for example, sodium tocopherol and its esters, peroxide dismutases, metal chelators, ascorbic acid and its esters, and the like.
  • Examples of anti-sebum agents include progesterone It is.
  • Examples of anti-acne agents include retinoic acid and benzoyl peroxide.
  • Examples of humectants include natural and synthetic ceramides, hyaluronic acid, cholesterol and its salts, collagens and the like.
  • CAPEs according to the present invention are used as an external preparation for skin, not only the treatment of skin diseases but also the prevention of skin diseases include, for example, facial, hand, foot or body cleansing and protection creams (for example, Dand Night Cream, It can be used in the form of a makeup remover cream, foundation cream, sunscreen cream), liquid foundation, makeup remover lotion, skin care body lotion, sunscreen lotion, skin care lotion, gel or foam.
  • skin diseases include, for example, facial, hand, foot or body cleansing and protection creams (for example, Dand Night Cream, It can be used in the form of a makeup remover cream, foundation cream, sunscreen cream), liquid foundation, makeup remover lotion, skin care body lotion, sunscreen lotion, skin care lotion, gel or foam.
  • FIG. 1 shows a comparison of the survival rates of SHRS P / izm rats fed CAPE and controls.
  • CAPE reduced mortality in SHRSP izm rats.
  • FIG. 2 is a graph comparing the weight ratio of the heart to the total weight of the SHRS PZizm rats fed CAPE and the control.
  • FIG. 3 is a graph comparing the weight ratio of the left ventricle to the total body weight of SH RSP / izm rats fed CAPE and the control.
  • FIG. 4 is a diagram comparing the weight ratio of the aorta to the total weight of the control with SHRS PZizm rats fed CAPE.
  • Figures 2 to 4 show that in each of the SHRS PZizm rats fed CAPE, the weight of each organ (heart, left ventricle, aorta) was reduced, and cardiac hypertrophy was suppressed.
  • FIG. 5 is a diagram comparing the expression rates of NF ⁇ -related genes in the left ventricle of SHRS P / izm rats fed CAPE and control.
  • FIG. 6 is a diagram comparing the expression rates of NF ⁇ B-related genes in SHRS P / izm rats fed CAPE and control aorta. The values in the figure show the expression ratio of the NF ⁇ B-related gene in SH RSP / izm rats relative to the control.
  • NF ⁇ -related genes indicate VCAM-1, awake, cyclinDK TNF-, IFN- ⁇ , IL-1
  • NF indicates a gene not related to KB.
  • SHRS P / izm rats fed CAPE had reduced NF ⁇ B-related gene expression in the left ventricle and aorta.
  • Test Example 4 In the same manner as in Test Example 1, Apo-E knockout mice (manufactured by TACONI C) were administered a powder feed containing CAPE every day until the 10th to 24th week, and blood was collected at the 24th week. Similarly, blood was collected at 24 weeks from Ap0-E knockout mice bred on a diet containing no CAPE and used as a control. Cholesterol and triglyceride levels in blood were measured with an automatic measuring machine (Mitsubishi Chemical).
  • FIG. 7 shows a comparison of cholesterol and triglyceride levels between Apo-E knockout mice fed with CAPE and controls.
  • the Apo_E knockout mice were administered a CAPE-containing powder feed every day until the 10-24 week calendar, and the aorta was removed at 24 weeks. Similarly, at 24 weeks, the aorta was removed from an Ap-E knockout mouse reared on a diet containing no CAPE and used as a control. Fat deposition in the aorta was evaluated by Oil red 0 staining (Mitsubishi Chemical).
  • FIG. 8 is a diagram comparing fat deposition in the aorta of Apo-E knockout mice fed with CAPE and control.
  • CAPE was able to suppress lipid deposition on the blood vessel wall without significantly lowering lipid.
  • FIG. 9 is a diagram comparing the expression rates of NF ⁇ -related genes in the aorta of Ap 0-E knockout mice fed CAPE and control aorta.
  • the values in the figure indicate the expression ratio of the NF ⁇ B-related gene in SHRS P / izm rats relative to the control.
  • NF KB-related genes indicate VCAM-1, ICAM, eye 1 in DK TNF-, IFN-r> IL-l / 3, IL-2, IL-6, N0S2, angiotensin II, and other genes. Indicates a gene that is not related to NF ⁇ B.
  • the expression rate of NF / cB-related genes was reduced in the aorta.
  • the agent according to the present invention was produced by thoroughly mixing 1 part by weight of CAPE and 99 parts by weight of lactose. Industrial applicability
  • the CAPEs according to the present invention hypertrophy of the heart can be suppressed without lowering blood pressure.
  • the inhibitor of the present invention is a revolutionary drug that acts only on cardiac hypertrophy.
  • deposition of lipids on the blood vessel wall can be suppressed. According to the present invention, dietary restriction and exercise for improving hyperlipidemia are unnecessary or reduced.
  • the prophylactic / therapeutic agent of the present invention may be used in addition to the above diseases, such as glaucoma, bronchial asthma, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.), and various skin problems. It is also effective in preventing and treating diseases.

Abstract

L'invention concerne une substance prophylactique/thérapeutique destinée aux complications par hypertrophie cardiaque de l'hyperlipidémie, du glaucome, de l'asthme bronchique, de l'arthrite rhumatoïde chronique, de la maladies intestinale inflammatoire, de la maladie d'Alzheimer ou des affections cutanées. Cette substance se caractérise en ce qu'elle contient un ester phénéthylique d'acide caféique.
PCT/JP2002/007400 2001-07-26 2002-07-22 Inhibiteur nf$g(k)b WO2003011276A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053671A1 (fr) * 2003-12-08 2005-06-16 Cheorl-Ho Kim Inhibiteur de mmp-9 contenant de l'acide caffeique ou de l'ester phenethylique d'acide caffeique
JP2005225872A (ja) * 2004-01-15 2005-08-25 National Institute Of Advanced Industrial & Technology アディポネクチン産生増進剤
KR101702897B1 (ko) * 2016-04-15 2017-02-06 가톨릭대학교 산학협력단 바이오틴이 결합된 카페인산 화합물을 유효성분으로 함유하는 통풍 예방 또는 치료용 조성물
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
US11433090B2 (en) 2017-06-16 2022-09-06 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

Citations (6)

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WO2005053671A1 (fr) * 2003-12-08 2005-06-16 Cheorl-Ho Kim Inhibiteur de mmp-9 contenant de l'acide caffeique ou de l'ester phenethylique d'acide caffeique
JP2005225872A (ja) * 2004-01-15 2005-08-25 National Institute Of Advanced Industrial & Technology アディポネクチン産生増進剤
KR101702897B1 (ko) * 2016-04-15 2017-02-06 가톨릭대학교 산학협력단 바이오틴이 결합된 카페인산 화합물을 유효성분으로 함유하는 통풍 예방 또는 치료용 조성물
WO2017179914A1 (fr) * 2016-04-15 2017-10-19 가톨릭대학교 산학협력단 Composition de prévention ou de traitement de la goutte, contenant un composé d'acide caféique étiqueté par la biotine en tant que substance active
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
US11433090B2 (en) 2017-06-16 2022-09-06 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

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