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WO2002072131A1 - Médicaments contre des affections hépatiques - Google Patents

Médicaments contre des affections hépatiques Download PDF

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Publication number
WO2002072131A1
WO2002072131A1 PCT/JP2002/001216 JP0201216W WO02072131A1 WO 2002072131 A1 WO2002072131 A1 WO 2002072131A1 JP 0201216 W JP0201216 W JP 0201216W WO 02072131 A1 WO02072131 A1 WO 02072131A1
Authority
WO
WIPO (PCT)
Prior art keywords
lskl
liver disease
drug
salt
liver
Prior art date
Application number
PCT/JP2002/001216
Other languages
English (en)
Japanese (ja)
Inventor
Sotaro Mushiake
Hiroki Kondou
Original Assignee
Ajinomoto Co., 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 Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Priority to JP2002571090A priority Critical patent/JPWO2002072131A1/ja
Publication of WO2002072131A1 publication Critical patent/WO2002072131A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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 relates to a novel liver disease drug containing LSKL (Leu-Ser-Lys-Leu) or a salt thereof as an active ingredient. It can be used as a drug for treatment, improvement, prevention of progress and prevention of various liver diseases (liver disease). Furthermore, the present invention also relates to treatment methods such as treatment, improvement, prevention of progress and prevention of liver diseases, and the use of specific active ingredients (the above-mentioned active ingredients) as drugs for liver diseases.
  • LSKL Leu-Ser-Lys-Leu
  • a salt thereof as an active ingredient.
  • hepatic diseases such as viral hepatitis, alcoholic hepatitis, non-alcoholic non-viral hepatitis, and other inflammatory liver diseases, and biliary atresia such as biliary atresia.
  • Hepatic parenchymal cells are damaged, causing liver fibrosis, resulting in portal vein hypertension, which leads to cirrhosis and liver failure.
  • TGF plays an important role in inducing fibrosis.
  • TGF] 3 is secreted as inactive latent TGF ⁇ and accumulated in the extracellular matrix. Therefore, it is considered that the regulation of TGF activity is mainly in the process of conversion from inactive latent TGF
  • Latent TGF iS is known to be converted to the active form by proteolytic enzymes such as plasmin, active oxygen, integrins, thrombospondin-1 (thr.mb. spndin-1; TSP-1), etc.
  • the activation molecule under physiological conditions has not been determined.
  • KRFK (Lys-Arg-Phe-Lys), a partial structure of TSP-1, interacts with LSKL of the N-terminal precursor peptide (LAP), which is a part of latent TGF] 3.
  • LAP N-terminal precursor peptide
  • TSP-1 is an important TGF j3 activator in vivo It has been shown to produce histological changes in the kidney and bronchus similar to those in quat mice (see Cell, 93, 1159-1170, 1998).
  • TSP-1 is not an activator of TGF 3 in platelets (see J, Bilo. Chem., 275, 17933-17936, 2000), and TSP-1. It has been controversial whether the regulation of TGF / 3 by physiology is universal in all organs.
  • the problem to be solved by the present invention is to provide an excellent drug (including a prophylactic agent) applicable to various liver diseases, in particular, hepatic fibrosis or hepatic parenchymal cell disorder that leads to such hepatic fibrosis.
  • the aim is to develop drugs that can be controlled. Disclosure of the invention
  • the present inventors have proposed that the above-mentioned tetrapeptide LSKL (hereinafter also referred to as “LSKL peptide”) has a fibrosis-suppressing action in the liver as well as a suppression of hepatic parenchymal cell degeneration and death, ie, an inhibitory action and a protective action.
  • the inventors have found that the present invention has been completed. That is, the present invention is directed to a liver disease drug, preferably a drug for suppressing hepatic parenchymal cell damage, more preferably a drug for suppressing hepatic fibrosis, which is characterized by containing the LSKL peptide or a salt thereof as an active ingredient.
  • a free form of LSKL and a salt can be used in combination, and this content is naturally included in the present invention.
  • LSKL stands for Leucyl-Seryl-Lysyl-Leu (Leu-Ser-Lys-Leu) and can be used in the present invention in the form of its salt (a pharmaceutically acceptable salt).
  • the amino acid constituting this tetrapeptide is preferably an IL-form which can be used for both L-form and D-form, and more preferably LSKL which is composed entirely of L-form amino acids. .
  • LSKL or its salt is used as an active ingredient in Honmei, but examples of salt include Examples of such salts include salts with organic or inorganic acids such as hydrochloric acid, sulfuric acid, and oxalic acid, and salts with pharmaceutically acceptable salts such as salts with organic and inorganic bases such as triethylammonium salt and sodium salt.
  • a liver disease drug is a liver disease or a drug used to prevent a liver disease, and more specifically, a drug used to treat, improve, prevent progression, prevent, or prevent liver disease. Is included.
  • Another aspect of the present invention is a method for treating a liver disease, which is characterized by administering LSKL or a salt thereof to a living body, such as treatment, amelioration, prevention of progression, and prevention of a liver disease. Method of treatment, improvement or prevention of ".” Furthermore, the present invention also provides a method for suppressing hepatic parenchymal cell damage or a method for suppressing hepatic fibrosis characterized by administering LSKL or a salt thereof to a living body.
  • the above-mentioned liver disease drug (including the above-mentioned hepatic parenchymal cell damage inhibitor and hepatic fibrosis inhibitor) can be adopted.
  • the present invention also includes, as yet another form, the use of LSKL or a salt thereof for a drug for liver disease.
  • LSKL a free form of LSKL and a salt thereof can be used in combination, and this content is naturally included in the present invention.
  • the drug for the liver disease (including the drug for inhibiting parenchymal cell damage and the drug for suppressing liver fibrosis) is as described above.
  • FIG. 3 illustrates the effect of inhibiting hepatocyte degeneration and death obtained in the examples.
  • the left side shows the results of the control group (physiological saline), and the right side shows the results of the LSKL-administered group (p ⁇ 0.01).
  • DMN dimethylnitrosamine
  • Saline saline
  • control group physiological saline
  • LSKL administration group is shown on the right side.
  • FIG. 1 is a diagram illustrating a change in body weight of an experimental animal SD rat obtained in an example.
  • ⁇ LSKL; Hata: Saline.
  • the vertical axis body weight (BW) (g); the horizontal axis: the number of days passed from the start of drug administration (Day).
  • Fig. 2 shows a survival curve of an experimental animal SD rat obtained in the example. ⁇ : LSKL; ⁇ : Saline.
  • the vertical axis survival rate (%); the horizontal axis: days elapsed from the drug administration start date (Day).
  • the subject to which the liver disease drug of the present invention is administered is not particularly limited as long as it seeks treatment, improvement, progress prevention, prevention, etc. of the liver disease, but is applicable to mammals, usually humans (patients). Is done.
  • liver disease there is no particular limitation on the type of liver disease to which the agent of the present invention is applied.
  • Representative liver diseases include viral hepatitis, alcoholic hepatitis, non-alcoholic nonviral hepatitis, inflammatory liver diseases such as autoimmune hepatitis, biliary atresia and other cholestatic liver diseases, cirrhosis, and liver failure And the like.
  • hepatic parenchymal cells are damaged for various reasons, resulting in and without cause fibrosis of the liver, resulting in portal vein pressure injuries, formation of varicose veins, cirrhosis, and liver failure It can be preferably applied to a liver disease that is likely to be transferred.
  • the LSKL peptide used in the present invention is known (see WO95 / 05191, etc.), and can be easily prepared based on a known method.
  • the LSKL peptide is prepared based on a production example described later. You can also.
  • the administration form of the drug of the present invention is not particularly limited. Therefore, various administration forms such as oral administration and parenteral administration (such as intravenous administration) can be adopted. The components are obtained as described above, but parenteral administration such as injection is preferred.
  • the dosage of the drug of the present invention is appropriately selected according to the type of liver disease, the degree of symptoms, the form of the preparation, and the like. You. For example, when the active ingredient LSKL peptide is administered by injection, the dose of the LSKL peptide to a patient per day is about 0.01 to 1 OOO mg, more preferably about 0.05 to 50 mg. More preferably, 0.1 to: about L 0 O mg can be used. In severe cases, the dose can be increased further.
  • the number and timing of administration can be once every few days or once a day, but it is usually several times a day, for example, divided into 2 to 4 times, or mixed and administered by infusion, etc. Can be administered.
  • oral administration it can be selected and administered on the basis of a dosage about 10 to 20 times that of the above injection administration.
  • the present invention can be used, for example, in combination or in combination with other drug components (pharmaceutically active substances).
  • the active ingredient intended in the present invention is contained and Any drug exhibiting pharmacological activity is included in the liver disease drug of the present invention.
  • compositions may also contain various pharmacologically acceptable substances for pharmaceuticals (as adjuvants, etc.).
  • Pharmaceutical substances can be appropriately selected according to the dosage form of the preparation, for example, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, lubricants, lubricants, Flavoring agents, sweetening agents, solubilizing agents and the like can be mentioned.
  • substances for preparation include magnesium carbonate, titanium dioxide, lactose, mannitol and other saccharides, talc, milk protein, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils, polyethylene glycol / And solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol.
  • the drug of the present invention can be prepared in various pharmaceutical forms known or developed in the future as described above, for example, various administration forms such as oral administration, intraperitoneal administration, transdermal administration, and inhalation administration. it can.
  • various administration forms such as oral administration, intraperitoneal administration, transdermal administration, and inhalation administration. it can.
  • known or future-developed methods can be appropriately employed.
  • compositions include, for example, appropriate solid or liquid preparation forms, Examples include granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops, injectable solutions, products which prolong the release of active substances, etc. Can be.
  • the drug of the present invention in the preparation form exemplified above should contain an effective amount of LSL of the above-mentioned component in order to exhibit a medicinal effect. Can be incorporated into the drug.
  • the present invention provides, as another form, a method for treating, ameliorating or preventing a liver disease, which is characterized by administering LSKL or a salt thereof to a living body, a method for suppressing hepatic parenchymal cell damage, or liver fibrosis.
  • the present invention also relates to a method for inhibiting the disease and, as yet another form, the use of LSKL or a salt thereof for a liver disease drug.
  • liver disease drug including the hepatic parenchymal cell damage inhibitor and the hepatic fibrosis inhibitor
  • hepatic parenchymal cell damage inhibitor and the hepatic fibrosis inhibitor
  • HMP-resin (lmmol, Wang-resin) was used, and ordinary Fmoc amino acid derivatives such as Leu, Ser (tBu), Lys (Boc) were used.
  • the amino acids used here were all in the L-form.
  • Deprotection of the resulting protected peptide and cleavage of the peptide from the resin carrier were carried out by trifluoroacetic acid treatment.
  • the crude peptide was precipitated with isopropyl ether, extracted with 0.1% aqueous trifluoroacetic acid, and the resin was removed by filtration to obtain a lyophilized product.
  • HM score hepatitis activity index score
  • c cross-linked fibrosis (pg vein-portal vein or portal vein-central vein), score 3;
  • the score between the score 1 and score 3 or a transitional type is defined as score 2.
  • Degeneration in the hepatic lobule. Specifically, the evaluation was made based on the following four criteria.
  • the finding which is considered to be an intermediate or transitional form between the score 1 and the score 3 is defined as the score 2.
  • the above results are shown in FIG. 1 (the effect of suppressing hepatocellular degeneration and death) and FIG.
  • the LSKL peptide-administered group had a significantly lower hepatocyte degeneration necrosis score than the saline-administered group. (P 0.01). Furthermore, as is clear from the results of FIG. 2, suppression of the liver fibrillation score was observed in the LSKL peptide-administered group.
  • LSKL peptide inhibited the degeneration and necrosis of liver parenchymal cells and fibrosis in a dimethylnitrosamine-induced liver injury fibrosis model. In addition, it is thought that the result led to improvement of general condition (increase in body weight and increase in survival rate). As is clear from the above results, it is understood that LSKL peptide is extremely superior as a drug for liver disease.
  • the invention's effect is very superior as a drug for liver disease.
  • an excellent drug for liver disease using the active ingredient can be provided.
  • it is useful as a drug capable of suppressing hepatic parenchymal cell damage and fibrosis.
  • the active ingredient is preferably administered in the form of the above-mentioned drug, and the above-mentioned disorder such as liver disease can be treated.
  • the present invention is extremely useful industrially, particularly in the fields of medicine, pharmaceuticals and the like.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne le recours au LSKL (Leu-Ser-Lys-Leu) ou son sel comme principe actif de médicaments donnant des résultats en traitement, amélioration ou prévention de pathologies hépatiques. Ces composés conviennent particulièrement comme médicaments permettant d'éviter des dégâts et la fibrose de cellules du parenchyme du foie. L'invention concerne également un procédé pour traiter des dégâts survenant notamment dans des pathologies hépatiques.
PCT/JP2002/001216 2001-03-12 2002-02-14 Médicaments contre des affections hépatiques WO2002072131A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2002571090A JPWO2002072131A1 (ja) 2001-03-12 2002-02-14 肝疾患治療薬

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-69055 2001-03-12
JP2001069055 2001-03-12

Publications (1)

Publication Number Publication Date
WO2002072131A1 true WO2002072131A1 (fr) 2002-09-19

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ID=18927143

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/001216 WO2002072131A1 (fr) 2001-03-12 2002-02-14 Médicaments contre des affections hépatiques

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JP (1) JPWO2002072131A1 (fr)
WO (1) WO2002072131A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117730A1 (fr) 2007-03-23 2008-10-02 Nisshin Pharma Inc. Composition pour empêcher ou traiter une maladie pulmonaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08333249A (ja) * 1995-06-07 1996-12-17 Ono Pharmaceut Co Ltd ＴＧＦ−β放出、活性化および合成抑制剤
JPH0930983A (ja) * 1995-07-19 1997-02-04 Tsumura & Co アポトーシス抑制剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08333249A (ja) * 1995-06-07 1996-12-17 Ono Pharmaceut Co Ltd ＴＧＦ−β放出、活性化および合成抑制剤
JPH0930983A (ja) * 1995-07-19 1997-02-04 Tsumura & Co アポトーシス抑制剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RIBEIRO S.M.F. ET AL.: "The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta", J. BIOL. CHEM., vol. 274, no. 19, 1999, pages 13586 - 13593, XP002951536 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117730A1 (fr) 2007-03-23 2008-10-02 Nisshin Pharma Inc. Composition pour empêcher ou traiter une maladie pulmonaire

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