WO2000071144A1 - Inhibiteur de la prolyl endopeptidase - Google Patents

Inhibiteur de la prolyl endopeptidase Download PDF

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Publication number
WO2000071144A1
WO2000071144A1 PCT/JP2000/003135 JP0003135W WO0071144A1 WO 2000071144 A1 WO2000071144 A1 WO 2000071144A1 JP 0003135 W JP0003135 W JP 0003135W WO 0071144 A1 WO0071144 A1 WO 0071144A1
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WO
WIPO (PCT)
Prior art keywords
rice
brown rice
prolyl endopeptidase
pep
inhibitor
Prior art date
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PCT/JP2000/003135
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English (en)
Japanese (ja)
Inventor
Hiroshi Kayahara
Kikuichi Tsukahara
Takeshi Inagaki
Original Assignee
Domer, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Domer, Inc. filed Critical Domer, Inc.
Priority to AU44337/00A priority Critical patent/AU4433700A/en
Priority to KR1020017014760A priority patent/KR20020019442A/ko
Publication of WO2000071144A1 publication Critical patent/WO2000071144A1/fr

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Classifications

    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides a prolyl endopeptidase inhibitor comprising a cereal extract as an active ingredient, a method for producing the prolyl endopeptidase inhibitor, a compound having a prolyl endopeptidase inhibitory activity, which is extracted and purified from a class II, A process for producing the compound, a prolyl peptidase inhibitor containing the compound, a food for preventing and / or improving cerebral dysfunction containing the compound, and a prophylactic and / or ameliorating cerebral dysfunction having prolyl peptidase inhibitory activity
  • the present invention relates to germinated brown rice and a food for preventing and / or improving brain dysfunction containing the germinated brown rice. Background art
  • senile dementia has become a serious social problem.
  • Senile dementia is mainly caused by the modulation of brain nerve cells itself (neurocellular disease dementia), and dementia caused by modulation of brain tissue other than brain nerve cells, such as blood clots in cerebral blood vessels.
  • Non-neurological dementia One type of neurological disease dementia is Alzheimer's disease (AD).
  • AD patients gradually eat their brains, develop symptoms such as wandering, incontinence, illusions, delusions, memory impairment, and personality collapse. Despite individual differences, death occurs 2 to 15 years after onset. AD patients do not have much impairment in their motor skills, so they may repeat wandering, etc., placing a heavy burden on caregivers.
  • AD Alzheimer's disease
  • prolylendopeptidase promotes the degradation of brain function-related peptides.
  • PEP prolylendopeptidase
  • Petit is a serine protease that has specificity for proline in the glycine chain and cleaves the peptide chain on the carboxyl group side of proline as shown in Fig. 1.
  • PEP cleaves and inactivates brain function-related peptides including proline, which functions to keep the brain normal, such as neurotransmitters such as substance P, neurotensin, and memory-related vasopressin and oxytocin. It is presumed to reduce brain function-related peptides, disrupt brain function, and cause AD. In fact, it has been shown that the amount of vasopressin in dementia patients is lower than in normal individuals [BIOI NDUSTRY 4: 788-796 (1987)].
  • substances that specifically inhibit PEP are expected to be applicable to the prevention and treatment of various disorders (eg, amnesia) caused by PEP, including AD, and N-acylpyrrolidine derivatives (JP-A-6-37764, JP-A-61-183297, JP-A-6-238775), synthetic inhibitors such as pyrrolidine amide derivatives [Japanese Patent Publication No. 7-64834], and PEP inhibitory peptides derived from sake lees [JP -77300] has been reported. However, PEP inhibitors derived from natural materials are required for safety and other aspects.
  • the present invention relates to a prolyl endopeptidase inhibitor comprising a cereal extract as an active ingredient, a method for producing the prolyl endopeptidase inhibitor, a compound extracted and purified from cereal having prolyl endopeptidase inhibitory activity, A production method, a prolyl endopeptidase inhibitor containing the compound, a food for preventing or improving cerebral dysfunction containing the compound, a germinated brown rice for preventing and / or ameliorating a cerebral dysfunction having prolyl endopeptidase inhibitory activity, And a food for preventing and / or improving cerebral dysfunction containing the sprouted brown rice.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, found a component that specifically inhibits PEP in rice, and succeeded in isolating and purifying the component from germinated brown rice. Thus, the present invention has been completed.
  • the present invention is a prolyl endopeptidase inhibitor containing a cereal extract as an active ingredient.
  • examples of the varieties include rice, wheat, corn, soybeans, my mouth, buckwheat, foam, fins, cane, sesame, and the like.
  • germinated rice eg, germinated brown rice
  • rice can be used as the rice.
  • the present invention is a method for producing a prolylendopeptidase inhibitor, which comprises extracting water and Z or an organic solvent (for example, hexane or the like) from cereals.
  • cereals include rice, wheat, corn, soybeans, my mouth, buckwheat, foam, fins, cane, sesame, and the like.
  • germinated rice eg, germinated brown rice
  • the present invention further provides the following formula ( ⁇ ) characterized by extracting and purifying from cereals:
  • CH3- (CH 2) 9-CH CH- (CH2) 6 / with a compound represented.
  • cereals include rice, barley, corn, soybeans, my mouth, buckwheat, foam, fins, cane, sesame, and the like.
  • germinated rice eg, germinated brown rice
  • the present invention is a prolyl endopeptidase inhibitor comprising the above compound as an active ingredient.
  • the present invention is a food for preventing and / or improving cerebral dysfunction, which comprises the above compound as an active ingredient.
  • the present invention relates to a brain dysfunction having prolyl endopeptidase inhibitory activity. Preventive and Z or improved germinated brown rice.
  • the present invention is a food for preventing and / or improving cerebral dysfunction, which comprises germinated brown rice having prolyl endopeptidase inhibitory activity.
  • This description includes part or all of the contents as disclosed in the description and / or drawings of Japanese Patent Application No. 11-138791, which is a priority document of the present application.
  • the present invention will be described in detail.
  • the PEP inhibitor of the present invention is a ketone or glyceride isolated and purified from rice different from conventional PEP inhibitors. This substance can be isolated and purified as follows.
  • Sources of the PEP inhibitor include cereals such as rice, wheat, corn, soybeans, my mouth, buckwheat, foam, millet, cane, and sesame, preferably brown rice, and most preferably germinated brown rice.
  • Rice-derived materials such as rice bran, rice germ, and rice bran oil can also be used.
  • rice brands include Koshihikari, Akitakomachi, and China No. 137, but the present invention is not limited to these.
  • Germinated brown rice can be prepared by immersing brown rice as a raw material in water or warm water adjusted to a temperature in the range of 5 to 50 ° C (preferably 30 to 34 ° C) for a certain period of time.
  • brown rice is first immersed in warm water, and when the brown rice grains have sufficiently absorbed water, the brown rice is taken out of the water or hot water bath and placed in an atmosphere of high humidity (for example, 100% relative humidity) for 5 hours to 5 days, preferably Leave to germinate for ⁇ 24 hours.
  • high humidity for example, 100% relative humidity
  • ozone having a bactericidal effect is dissolved in warm water, it is possible to suppress the growth of general bacteria, Escherichia coli, and viruses during immersion.
  • air containing ozone generated by an ozone generator eg, Ozone 0Z-2-A 100-30 type ozone generator
  • the degree of germination is such that the swelling or protrusion before and after awakening is visible in the embryo part. Is ideal.
  • the brown rice is dried or heat-treated, or stored refrigerated or frozen below 6 ° C.
  • the PEP inhibitory activity of Class I components is measured by examining the difference in the substrate degradation rate when a synthetic substrate having a proline residue in the molecule or a natural substrate is degraded in the presence or absence of a sample containing an inhibitor. can do.
  • synthetic substrates that can be used include ZGly-Pro-p-nitroanilide (Z-Gly-Pro-pNA), ZGly-Pro-2-naphthylamide, and Z-Gly- Pro-4-methylcoumarinamide and other C-termini with a degradation indicator attached to it, and natural substrates such as oxytocin and thyroid-stimulating hormone-releasing hormone can be used as natural substrates.
  • Z-Gly-Pro-pNA ZGly-Pro-p-nitroanilide
  • Z-Gly-Pro-2-naphthylamide Z-Gly-Pro-4-methylcoumarinamide and other C-termini with a degradation indicator attached to it
  • natural substrates such as oxytocin and thyroid-stimulating
  • the separation of the PEP inhibitor from the source described in (1) above can be performed as follows. That is, first, the sampling source is ground as it is or using a mortar or a ball mill. Then, osmotic extraction is performed with a solvent (eg, distilled water, methanol, ethyl acetate, n-hexane, etc.). Then, the obtained extract is concentrated to dryness using an evaporator or the like, and then dissolved in an appropriate solvent.
  • a solvent eg, distilled water, methanol, ethyl acetate, n-hexane, etc.
  • the lysate is applied to a chromatography column using silica gel or the like as a carrier, and eluted with an appropriate solvent (for example, a mixture of ethyl acetate and Zn-hexane), and the fraction having PEP inhibitory activity is separated.
  • an appropriate solvent for example, a mixture of ethyl acetate and Zn-hexane
  • the crude product is roughly refined.
  • PEP inhibitors can be isolated by subjecting the crude product to thin-layer chromatography or high-performance liquid chromatography.
  • the structure of the compound isolated in (3) above must be determined by instrumental analysis combining IR spectrum, 13 C-NMR, ⁇ ⁇ correlation two-dimensional NMR (C0SY; correlative ion spectroscopy), etc. Can be. Once the chemical structure of the present invention has been determined, the PEP inhibitor of the present invention can be obtained by chemical synthesis thereafter. 2. Use of the PEP inhibitor of the present invention as a food material
  • the PEP inhibitor of the present invention may be used for the production of foods for specified health use suitable for preventing or improving cerebral dysfunctions such as Alzheimer's disease and amnesia caused by degradation of brain function-related peptides by PEP.
  • solid foods include bread dough; dough for baked confectionery such as rice crackers, biscuits, and cookie; buckwheat, udon, etc .; fish products such as kamaboko and chikuwa; livestock meat products such as ham and sausage; powdered milk Is mentioned.
  • the jelly-like food include fruit jelly and coffee jelly.
  • examples of the liquid food include tea; coffee; black tea; fermented milk; Tea, which has been widely used for drinking, especially as brown rice tea, accounts for a large portion of the tea that has the unique flavor of rice and is consumed on a daily basis.
  • Genmaicha is usually produced by drying and roasting steamed brown rice and / or white rice.By using germinated brown rice instead of milled rice, it is possible to produce brown rice tea that has a dementia-preventing effect. it can.
  • the PEP inhibitor of the present invention When the PEP inhibitor of the present invention is added to the above food, it may be used not only in the form of isolated and purified food, but also in the form of a rice extract, brown rice or germinated brown rice crude extract or powdered product containing the PEP inhibitor. Can be.
  • the amount added to the food is 0.01 to 1% by weight when isolated and purified, preferably 0.1 to 0.5% by weight, and 0 when crude extract is used. 001 to 0.1% by weight, preferably 0.005 to 0.05% by weight, and 1 to 10% by weight, preferably 2 to 5% by weight when a powder is used. Since the amount of addition varies depending on the type and shape of the food, the food subject, and the like, it can be added outside the above range.
  • germinated brown rice has a remarkably higher PEP inhibitor content than polished rice or unpolished brown rice, so that germinated brown rice is used as a normal diet to prevent Alzheimer's disease or amnesia. Alternatively, it can be used as food such as mochi or porridge. 3.
  • the compound of the present invention Since the compound of the present invention has an activity of inhibiting PEP, it can be applied to patients by oral or parenteral administration as a pharmaceutical composition such as an anti-Alzheimer's agent and an anti-amnesic agent.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier or additive.
  • carriers and additives include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch.
  • the additives to be used are appropriately or in combination selected from the above depending on the dosage form of the present invention.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered orally, it can be used in the form of solid preparations such as tablets, granules, powders and pills, or liquid preparations such as liquids and syrups.
  • granules and powders can be in unit dosage form as capsules, or in the case of liquid preparations, as dry products to be re-dissolved when used.
  • solid preparations usually contain additives such as binders, excipients, disintegrants, wetting agents, lubricants and the like, which are generally used in preparations, in their compositions.
  • Liquid preparations usually contain additives such as stabilizers, buffers, preservatives, fragrances, coloring agents, and flavoring agents which are generally used in the preparations.
  • the pharmaceutical composition of the present invention when administered parenterally, it can be used in the form of injections, suppositories and the like.
  • injections in particular, in the case of injections, they are usually provided in unit dose ampoules or multi-dose containers.
  • a suitable carrier for example, sterile pyrogen-free water. You may.
  • These dosage forms usually contain additives, such as emulsifiers and suspending agents, which are generally used in pharmaceutical compositions in their compositions.
  • the injection method include intravenous drip intravenous injection, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and intradermal injection.
  • the dosage varies widely depending on the age of the subject, the route of administration, and the number of administrations. be able to. In general, it is desirable to administer the active ingredient per adult in the range of 1 to 10 mg at a time for oral administration and 10 to 50 mg at a time for parenteral administration.
  • the anti-dementia effect of the compound of the present invention was determined by a conventional rat vagus test ⁇ a rat passive avoidance learning test [Int. Symp. On Pharmacology of Learning and Memory (1981)]. You can find out.
  • a rat to which a compound of the present invention was administered was placed on a platform in a passive avoidance test box consisting of a grid electrode floor and a platform. Rats to which water was administered, and 3 as a positive control, rats to which Z-prolyl-lipinal, which is known to have PEP inhibitory activity, were placed. Keep flowing until it rises.
  • the rat remains on the platform for more than 20 seconds, the rat is considered to have learned and is removed from the box.
  • amnesia is artificially induced by administering the amnesia-inducing agent scopolamine hydrobromide to the learning rats. Then place them again on the evacuation platform in the passive avoidance test box and measure the time remaining on the platform. Accordingly, when the staying time of the rats administered with the compound of the present invention in 1) is significantly longer than the staying time of the negative control rats in 2), it is considered that the compound of the present invention has an anti-amnesic effect. If there is no significant difference in the stay time, it is evaluated that there is no anti-amnesic effect.
  • FIG. 1 is a diagram showing degradation points of functional brain peptides by prolylendopeptidase.
  • FIG. 1 shows the relationship between PEP inhibitory activity and extraction time in various solvent extracts of germinated brown rice.
  • FIG. 3 is a graph showing the relationship between PEP inhibitory activity in n-hexane extract of white rice, brown rice and germinated brown rice and extraction time.
  • PEP inhibitor was extracted from germinated brown rice using various solvents.
  • brown rice brand name: Nagano Koshihikari
  • Nagano Prefecture was washed with water and germinated in 21 hours using a microcomputer electric germinator (manufactured by Takekoshi Manufacturing Co., Ltd.).
  • a microcomputer electric germinator manufactured by Takekoshi Manufacturing Co., Ltd.
  • To about 450 g of the germinated brown rice thus obtained 1200 ml of distilled water, methanol, ethyl acetate or n-hexane was added, and osmotic extraction was performed. Every five days after the start of the extraction, each extract was collected, and the solvent was evaporated using an evaporator to obtain an extract.
  • the PEP inhibitory activity was measured by the method of Yoshimoto et al. [ ⁇ ⁇ Yoshimoto: Bioch im. Biophys. Acta, 569: 184-189 (1979)]. That is, first, 0.1 g of each extract obtained in Example 1 was sufficiently dissolved in 2 ml of a 40% aqueous dioxane solution to prepare a sample solution. Also, a substrate solution was prepared by dissolving Z-Gly-Pro-pNA in 40% dioxane to a concentration of 2 mM.
  • the enzyme is obtained by dissolving PEP (Funakoshi) derived from Flavobacterium meningosepticum at a concentration of 0.175 U / ml in 0.05 M sodium phosphate buffer (PH 7.0). A solution was prepared. Further, an enzyme reaction stop solution was prepared by dissolving 10 g of TritonX-100 in 95 ml of 1 M sodium acetate buffer. Such enzyme activity measuring solution obtained in the carrying out the reaction in pairs formed and order shown in Table 1, after the completion of the reaction, 0D 4i of each reaction mixture. was measured. Table 1 Reaction system for measuring PEP inhibitory activity
  • PEP inhibitory activity (%) ⁇ ( ⁇ - ⁇ ') — (S-S') ⁇ ⁇ (B-B ') X100
  • n-hexane extract or components that inhibit PEP exist many compared to extracts of other solvents, or high PEP inhibitory capacity component having the hexane extract to n- was considered only to be included.
  • High inhibitory activity was observed not from distilled water extract but from organic solvent extract, suggesting that fat-soluble substances are involved in PEP inhibition.
  • the C-2 compound was a triglyceride having a partial structure such as ⁇ ( ⁇ ⁇ ⁇ ) below.
  • C-3 is a 7-octadecenyl-7,10-hexane having a structure like the following (II), The geninole ketone (7-octadeceny l-7, 10-hen i cosad i eny l ketone) was identified.
  • Example 5 Comparison of PEP inhibitory activity of n-hexane extract of polished rice, brown rice, and germinated brown rice In germinated brown rice, high PEP inhibitory activity was observed from n-hexane extract. Extracted n-hexane and compared with germinated brown rice Extracted white rice and brown rice immersed in distilled water for 21 hours with n-hexane respectively Extracted white rice and brown rice as well as germinated brown rice The ratio of the extraction solvent was 1200 ml to about 450 g. The PEP inhibitory activity of each extract was measured every 5 days after the start of permeation extraction, and the dissolution concentration at this time was 0.1 g of the extract. The ratio of the 40% aqueous dioxane solution was 2 ml. The results of the PEP inhibitory activity of each solvent extract are shown in FIG.
  • a prolyl endopeptidase inhibitor comprising a cereal extract as an active ingredient, a method for producing the prolyl endopeptidase inhibitor, A compound having prolylendopeptidase inhibitory activity, a process for producing the compound, a prolyl endopeptidase inhibitor containing the compound, a food for preventing and / or improving cerebral dysfunction containing the compound, prolylend A germinated brown rice having a peptidase inhibitory activity for preventing and / or improving cerebral dysfunction, and a food for preventing and / or improving cerebral dysfunction containing the germinated brown rice are provided.
  • INDUSTRIAL APPLICABILITY The present invention is useful for alleviating the symptoms of patients with cerebral dysfunction (eg, dementia, amnesia, etc.). All publications cited herein are incorporated herein by reference in their entirety.

Abstract

L'invention concerne un inhibiteur de la prolyl endopeptidase contenant un extrait de céréales faisant office de principe actif; un procédé d'obtention de cet inhibiteur; un composé ayant une activité inhibant la prolyl endopeptidase qui est extraite de céréales et purifiée; un procédé d'obtention de ce composé; un inhibiteur de la prolyl endopeptidase contenant ledit composé; des aliments permettant de prévenir et/ou de soulager les troubles cérébraux contenant ledit composé; du riz brun de germination permettant de prévenir et/ou de soulager les troubles cérébraux faisant preuve d'une activité inhibant la prolyl endopeptidase et des aliments permettant de prévenir et/ou de soulager les troubles cérébraux contenant ledit riz brun.
PCT/JP2000/003135 1999-05-19 2000-05-16 Inhibiteur de la prolyl endopeptidase WO2000071144A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU44337/00A AU4433700A (en) 1999-05-19 2000-05-16 Prolyl endopeptidase inhibitor
KR1020017014760A KR20020019442A (ko) 1999-05-19 2000-05-16 프롤릴 엔도펩티다제 저해제

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/138791 1999-05-19
JP13879199A JP3148739B2 (ja) 1999-05-19 1999-05-19 プロリルエンドペプチダーゼ阻害剤

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KR (1) KR20020019442A (fr)
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AU (1) AU4433700A (fr)
WO (1) WO2000071144A1 (fr)

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WO2003015804A1 (fr) * 2001-08-17 2003-02-27 David Rudov Traitement permettant d'ameliorer le fonctionnement du systeme nerveux central
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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KR20030068993A (ko) * 2002-02-19 2003-08-25 박희원 치매와 비만예방 및 치료 가능한 주식 조성물 제조방법.
US20080260873A1 (en) * 2007-04-23 2008-10-23 Fancl Corporation Agent for prevention or improvement of neuropathy comprising pre-germinated brown rice lipid fraction as an effective ingredient
KR101352396B1 (ko) 2010-12-29 2014-01-17 전북대학교산학협력단 1,3-다이팔미토일-2-올레오일글라이세롤을 유효성분으로 포함하는 뇌질환 치료 또는 예방용 조성물
CN105254498B (zh) * 2014-07-18 2017-11-21 浙江康莱特药业有限公司 化合物1,3‑二油酸‑2‑亚油酸甘油酯、制剂、制备方法及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0937719A (ja) * 1995-07-31 1997-02-10 Gekkeikan Sake Co Ltd 経口摂取物
JPH0940693A (ja) * 1995-07-31 1997-02-10 Gekkeikan Sake Co Ltd プロリルエンドペプチダーゼ阻害剤
JPH1077300A (ja) * 1996-09-04 1998-03-24 Gekkeikan Sake Co Ltd プロリルエンドペプチダーゼ阻害ペプチド

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0937719A (ja) * 1995-07-31 1997-02-10 Gekkeikan Sake Co Ltd 経口摂取物
JPH0940693A (ja) * 1995-07-31 1997-02-10 Gekkeikan Sake Co Ltd プロリルエンドペプチダーゼ阻害剤
JPH1077300A (ja) * 1996-09-04 1998-03-24 Gekkeikan Sake Co Ltd プロリルエンドペプチダーゼ阻害ペプチド

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SUSUMU MARUYAMA ET AL.: "Prolyl endopeptidase inhibitory activity of peptides in the repeated sequence of various proline-rich proteins", JOURNAL OF FERMENTATION AND BIOENGINEERING, vol. 74, no. 3, 1992, pages 145 - 148, XP002946660 *
SUSUMU MARUYAMA: "Proline-specific peptidases and proline-containing biologically active peptides", REPORT OF THE FERMENTATION RESEARCH INSTITUTE (YATABE): RESEARCH REPORT OF NATIONAL INSTITUTE OF BIOSCIENCE AND HUMAN-TECHNOLOGY, AGENCY OF INDUSTRIAL SCIENCE AND TECHNOLOGY, no. 75, 1992, pages 131 - 145, XP002946659 *
YOSHIYUKI SAITO ET AL.: "Prolyl endopeptidase inhibitors in sake and its byproducts", J. AGRIC. FOOD. CHEM., vol. 45, no. 3, 1997, pages 720 - 724, XP002946661 *

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WO2003015804A1 (fr) * 2001-08-17 2003-02-27 David Rudov Traitement permettant d'ameliorer le fonctionnement du systeme nerveux central
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
US7897633B2 (en) 2004-02-05 2011-03-01 Probiodrug Ag Inhibitors of glutaminyl cyclase
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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KR20020019442A (ko) 2002-03-12

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