WO2019190214A1 - Composition pharmaceutique pour la prévention ou le traitement de la fibrose - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de la fibrose Download PDF

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WO2019190214A1
WO2019190214A1 PCT/KR2019/003619 KR2019003619W WO2019190214A1 WO 2019190214 A1 WO2019190214 A1 WO 2019190214A1 KR 2019003619 W KR2019003619 W KR 2019003619W WO 2019190214 A1 WO2019190214 A1 WO 2019190214A1
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Prior art keywords
hydroxy
methyl
naphthalen
yloxy
octendiamide
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PCT/KR2019/003619
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English (en)
Korean (ko)
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조중명
김광수
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크리스탈지노믹스(주)
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Priority claimed from KR1020190034855A external-priority patent/KR20190113639A/ko
Application filed by 크리스탈지노믹스(주) filed Critical 크리스탈지노믹스(주)
Priority to JP2020545550A priority Critical patent/JP2021516683A/ja
Priority to RU2020132922A priority patent/RU2020132922A/ru
Priority to EP19774914.6A priority patent/EP3777847A4/fr
Priority to CN201980020179.8A priority patent/CN111867571A/zh
Priority to BR112020017776-8A priority patent/BR112020017776A2/pt
Priority to US16/982,309 priority patent/US20210015772A1/en
Priority to CA3093779A priority patent/CA3093779A1/fr
Publication of WO2019190214A1 publication Critical patent/WO2019190214A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of fibrosis containing alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide, derivatives thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Fibrosis means high deposition of fibrous connective tissue, which is due to an imbalance between proliferation and degradation of fibrous tissues.
  • a common feature of these diseases is the hyperproliferation of fibrotic cells.
  • Tissue and organ fibrosis are often multiple organs caused by pulmonary fibrosis, liver fibrosis, chronic pancreatitis, scleroderma, renal glomerular fibrosis and radiochemistry and tissue transplantation. Fibrosis is included.
  • Renal fibrosis is a scar that accumulates due to inflammation in the kidney tissue, which causes fibrosis. A part of the kidney is hardened and its function is lost. This leads to chronic renal failure, which is accompanied by anemia, coagulation disorders, hypertension, various complications and infections of the cardiopulmonary and gastrointestinal tract. If kidney function is less than 15% of normal people, erythropoietin production in the kidney is lowered, leading to decreased red blood cell production. In addition, urinary secretion caused by urine secretion does not occur actively, reducing the life of erythrocytes causes strong anemia. There is also an increased risk of developing systemic infection with the development of uremia, which is a major factor in the development of sepsis.
  • Pulmonary fibrosis is known to be caused by idiopathic pulmonary fibrosis (IPF). It is known to cause stimulation of epithelial cells or target cells continuously, causing damage and causing abnormalities in the healing process, but the stimulating factors are not known. However, the inflammation of the lung does not directly cause pulmonary fibrosis, but it is known that pulmonary fibrosis is caused by the difference between a patient with idiopathic pulmonary fibrosis and a normal person in the process of pulmonary inflammation first and then healing to normal tissue. Another major mechanism of fibrosis is the activation and proliferation of fibroblasts by T helper type 2 cytokines, leading to the deposition and fibrosis of extracellular matrix.
  • T helper type 2 cytokines leading to the deposition and fibrosis of extracellular matrix.
  • Liver fibrosis can be defined as an excessive deposition of extracellular matrix due to chronic intra-inflammatory inflammation, which results in alteration of intrahepatic structure and a decrease in hepatocyte counts when chronic liver disease persists due to excessive deposition of such extracellular matrix. This leads to cirrhosis.
  • Representative cells involved in liver fibrosis include hepatic stellate cells, Kupffer cells, and endothelial cells. Hepatic stellate cells are activated as a major producer of extracellular matrix and are involved in the production of various extracellular matrix, including collagen.
  • Cooper cells exist in the sinusoidal space of the liver, and substances produced from activated Cooper cells affect surrounding hepatocytes, endothelial cells, and hepatic stellate cells to promote liver fibrosis.
  • endothelial cells are also involved in the production of growth factors and extracellular matrix involved in the proliferation of hepatic stellate cells by inflammation or liver fibrosis.
  • Cytokines that affect liver fibrosis include transforming growth factor- ⁇ (TGF- ⁇ ) and platelet derived growth factor (PDGF).
  • TGF- ⁇ is the most potent fibrosis-promoting cytokine of hepatic stellate cells, and hepatic stellate cells themselves are the major producers of TGF- ⁇ .
  • PDGF is the most potent dividing and proliferating cytokine of hepatic stellate cells.
  • the liver fibrosis process has long been recognized as an irreversible phenomenon, but it has recently been reported that it can be reversibly changed, allowing for dynamic changes and precisely measuring these changes has become clinically very important.
  • the present inventors have completed the present invention by confirming the effects of alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide, derivatives thereof, or pharmaceutically acceptable salts thereof of certain formulas on inhibiting and improving fibrosis.
  • An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of fibrosis containing alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide, derivatives thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of fibrosis comprising a compound of Formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is halophenyl, C 1- 3 alkoxy, C 1- 3 alkoxy C 1 - 3 alkyl, cyclohexane yl, furanyl, thiophenyl, imidazole, imidazolidine pyridyl C 1 - 3 alkyl, C 1-3 alkylamino, di-C 1 - 3 alkyl, hydroxy, phenyl, tetrahydro furanyl, cyclohexyl, cyclohexenyl, oxopyrrolidin pyridinyl, C 1-3 alkoxy-phenyl, di-C 1 - 3 alkyl-aminophenyl , C 1- 3 alkyl and pyrrolidinyl-trifluoromethoxyphenyl C 1- 3 alkyl optionally substituted with one or more substituents selected from the group consisting of; Pyrrolidine-3-alkyl, benzyl, C 1- 3 alkyl or C 3-
  • the compound of Formula 1 is selected from the group consisting of the following compounds.
  • the compound of formula 1 is represented by the following formula (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yljade) Methyl) oct-2-enediamide ((E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalen-1-yloxy) methyl) oct-2-enediamide) yl Can be.
  • the fibrosis may be renal fibrosis.
  • the fibrosis can be pulmonary fibrosis, and the pulmonary fibrosis can be induced with a humidifier fungicide component as well as a general bleomycin induction model.
  • the humidifier disinfectant components include polyhexamethylene guanidine (PHMG), chloromethyl isothiazolinone (CMIT), methyl isothiazolinone (MIT), ethoxyethyl guanidine ( Oligo (2- (2-ethoxy) ethoxyethyl guanidinium chloride, PGH) and the like.
  • the pulmonary fibrosis includes bleomycin, polyhexamethylene guanidine (PHMG), chloromethylisothiazolinone (CMIT), methylisothiazolinone (MIT) and ethoxyethylguadiin chloride ( PGH) may be derived to include one or more selected from the group consisting of.
  • PHMG polyhexamethylene guanidine
  • CMIT chloromethylisothiazolinone
  • MIT methylisothiazolinone
  • PGH ethoxyethylguadiin chloride
  • the fibrosis may be liver fibrosis.
  • the pharmaceutically acceptable salts are phosphate, tartarate, stearate, gluconate, fumarate, naphthoate, and 1-hydroxy-2-naphthoate (1-Hydroxy- 2-naphthoic acid) may be one or more selected from the group consisting of.
  • compositions according to the invention may be in the form of capsules, tablets, granules, injections, ointments, powders or beverages.
  • the pharmaceutical composition according to the invention may be targeted at humans.
  • the pharmaceutical composition according to the present invention is not limited thereto, but may be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, capsules, tablets, and aqueous suspensions, respectively, according to conventional methods.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be used as oral administration binders, suspending agents, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, flavorings, etc., in the case of injections, buffers, preservatives, analgesic Topical agents, solubilizers, isotonic agents, stabilizers and the like can be mixed and used, and for topical administration, bases, excipients, lubricants, preservatives and the like can be used.
  • the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration may be in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, in the case of injections, in unit dosage ampoules or multiple dosage forms. have. And other solutions, suspensions, tablets, capsules, sustained release preparations and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited to these, but not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intramuscular, intrasternal, intradural, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • the pharmaceutical composition according to the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, bronchial inhalation, intrauterine dural or intracerebroventricular injection.
  • compositions of the present invention vary depending on a number of factors, including the activity, age, weight, general health, sex, formulation, time of administration, route of administration, rate of release, drug combination and severity of the particular disease to be prevented or treated, of the specific compound employed.
  • the dosage of the pharmaceutical composition may be appropriately selected by those skilled in the art depending on the patient's condition, weight, degree of disease, route of administration, and duration, and may be 0.0001 to 50 mg / kg or 0.001 to 1 day. It may be administered at 50 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
  • Pharmaceutical compositions according to the invention may be formulated as pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions.
  • the amount of the compound of Formula 1, which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, weight, and disease of the patient, but is preferably 0.01 to 100 mg / kg, preferably 0.1 to 50 mg / kg. It may be administered once to several times daily.
  • the dosage of the compound of Formula 1 according to the present invention may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the dosage of the compound of Formula 1 according to the present invention may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition according to the present invention ⁇ in the renal fibrosis animal model induced by acute renal failure and pulmonary fibrosis animal model induced by bleomycin (Bleomycin), polyhexamethylene guanidine (PHMG) and the like fibrosis marker ⁇
  • Bosmycin bleomycin
  • PHMG polyhexamethylene guanidine
  • SMA alpha-smooth muscle actin
  • Figure 1 shows (E) -N1- (3- (dimethylamino) propyl) -N8-hydroxy-2-((naphthalene-1) at 30 mg / kg / day in an animal model induced by acute renal failure.
  • -Iloxy) methyl) oct-2-enediamide compound of Formula 2, hereinafter referred to as "CG200745"
  • CG200745 a compound of Formula 2, hereinafter referred to as "CG200745”
  • Figure 2 shows the renal tissue of acute renal failure induced kidney fibrosis animal model intake of 30 mg / kg / day of CG200745 in the renal tissue of the CG200745 intake group or the solvent control group in the left kidney tissue cells of the normal kidney animal model It is a graph comparing the amount of ⁇ -SMA (alpha-smooth muscle actin) expression by performing the real-time polymerization effect chain reaction of the separated RNA.
  • ⁇ -SMA alpha-smooth muscle actin
  • Fig. 3 shows histopathology of lung tissue sections and hemotoxylline & eosin staining of a CG200745-administered or solvent-controlled group administered 15,30,60 mg / kg / day CG200745 in a bleomycin-induced lung fibrosis animal model. Results of the analysis.
  • Figure 4 compares the concentration of collagen by Sircol assay with bronchial lung cell lavage fluid of CG200745 administration group or solvent control group administered 15,30,60 mg / kg / day CG200745 in bleomycin-induced lung fibrosis animal model One graph.
  • FIG. 6 shows lung tissue sections, hemotoxine & eosin staining and Masson trichrome staining of CG200745-administered or solvent-controlled groups treated with CG200745 at 1,15,30,60 mg / kg / day in PHMG-induced lung fibrosis animal model. This is the result of histopathological analysis.
  • Figure 7 shows the Sircol assay in bronchoalveolar lavage fluid (BALF) of CG200745 administration group or solvent control group administered CG200745 at 1,15,30,60 mg / kg / day in PHMG-induced lung fibrosis animal model. This is a graph comparing the concentration of collagen.
  • BALF bronchoalveolar lavage fluid
  • the extracted normal kidneys and kidneys caused by acute renal failure were fixed with 4% paraformaldehyde, covered with paraffin, and tissue sections were prepared to a thickness of 3 ⁇ m. Hematoxylin & eosin staining was performed on the finished tissue sections for renal histopathological analysis. For hematoxylin staining, kidney tissue sections were stained with Gill ⁇ s hematoxylin for 5 minutes, washed with tap water, and treated with 95% ethanol. Eosin staining was stained with eosin and phloxine for 1 minute. The tissue sections were then dehydrated with ethanol and xylene and fixed with Canada balsam. The prepared kidney tissue sections were observed under an optical microscope. As a result, as shown in FIG.
  • fibrosis marker ⁇ -SMA alpha-smooth muscle actin
  • RNA was isolated from the isolated kidney and the kidneys of the CG200745-ingested group, which was the kidney that caused acute renal failure, and synthesized cDNA by reverse transcription, followed by real-time PCR, which is a fibrosis marker.
  • the expression levels of ⁇ -SMA alpha-smooth muscle actin
  • Kidney cortex was homogenized with Trizol solution (Invitrogen, Carlsbad, Calif.). RNA was extracted from the homogenized kidney cortex using chloroform, precipitated with isopropanol, and washed with 75% ethanol. The washed RNA was dissolved in distilled water, and the concentration was confirmed by measuring absorbance at 260 nm (Ultraspec 2000; Pharmacia Biotech, Cambridge, UK). cDNA was prepared by reverse transcription of 5 mg RNA using oligo (dT) primer and superscript reverse transcriptase II (Invitrogen, Carlsbad, CA). The produced cDNA was quantified by SYBR Green using Smart Cycler II System (Cepheid, Sunnyvale, CA).
  • Real-time polymerase chain reaction was performed by mixing 10 mM forward primer, 10 mM reverse primer, 2X SYBR Green Premix Ex Taq (TAKARA BIO INC, Seta 3-4-1, Japan), 0.5 mL cDNA, and the final volume was 20 mL. Distilled water was added to this end.
  • Real-time polymerase chain reaction was performed using the Rotor-Gene TM 3000 Detector System (Corbette research, Mortlake, New South Wales, Australia), and the relative quantification of ⁇ -SMA mRNA was compared.
  • Steps 2) to 5) were repeated 64 times, and the final cycle final temperature was increased from 60 ° C to 95 ° C to form a melting curve. PCR expression comparison was confirmed by the SYBR Green measurement value. The following primer sequences were used:
  • Human ⁇ -SMA forward 5′-ACTGGGACGACATGGAAAAG-3 ′, 5′-CATCTCCAGAGTCCAGCACA-3 ′, human GAPDH forward, 5′-TGTGTCCGTCGTGGATCTGA-3 ′ and 5-GATGCCTGCTTCACCACCTT-3 ′.
  • the CG200745-intake group in which 30 mg / kg of CG200745 was ingested in kidneys caused by ureter obstruction was found to have a 50% or more decrease in ⁇ -SMA expression than the solvent control group. .
  • the bleomycin model was carried out using 7-week-old C57BL / 6 female mice, and divided into 5 groups of CG500745 15, 30, 60 mg / kg and a control group after bleomycin administration, bleomycin administration.
  • the airways of the mice were dissected and 2 mg / kg bleomycin was injected into the airways at a volume of 50 ⁇ l. After injection, the incision site was closed with 5-0 nylon. Following bleomycin injection, drug administration was intraperitoneally administered for a total of two weeks.
  • mice were thoracic and lungs were removed and fixed with 4% paraformaldehyde. Soak it in 4% paraformaldehyde for 48 hours, fix it at 4 °C, make paraffin block, cut the paraffin embedding tissue into 4 ⁇ m, and attach it to the slide. Hemotoxiline & eosin staining and Masson's trichrome staining were performed.
  • Hemotoxiline & eosin staining was performed twice with slides of xylene for 5 minutes, ethanol 100%, 95% and 70% for 2 minutes and washed in flowing distilled water. After washing, the slides were soaked in hematoxylin for 1 minute, washed several times in flowing distilled water, and then immersed in eosin for 30 seconds and washed several times with flowing distilled water. Then, 1 minute each in 70%, 95% and 100% ethanol, and soaked 2 times in xylene for 2 minutes. Finally, the cover-slide was permanently attached using mounting medium xylene, and these samples were observed through an optical microscope.
  • Masson's trichrome staining was performed to stain collagen and muscle fibers. Slides were washed twice with xylene for 5 minutes, ethanol 100%, 95%, and 70% for 2 minutes and washed in flowing distilled water. After washing, the slide was adjusted to 56 ⁇ 64 ° C. in a constant temperature water bath, and then reacted with Bouin's fluid for 1 hour and then cooled for 10 minutes. After washing several times in flowing distilled water, iron hematoxylin 5 minutes and rinsed in warm water for 2 minutes, then washed once more with distilled water. 5 minutes staining with Biebrich scarlet / Acid Fuchsin solution and washing with distilled water.
  • the airway skin of the mouse was incised, the airways were exposed, 800 ⁇ l of PBS was put into the trachea, and 500 ⁇ l was recovered again to obtain a bronchoalveolar lavage fluid.
  • the bronchial alveolar lavage fluid was centrifuged at 4 ° C., 1,200 rpm for 5 minutes, and then the supernatant was obtained. 50 ⁇ l of bronchoalveolar lavage fluid and 1 ml of sircol dye reagent were mixed for 30 minutes. After centrifugation at 4 ° C.
  • Tissue pulmonary fibrosis and related markers ( ⁇ -SMA, collagen I, PAI-1, E-cadherin, N-cadherin) and western blot were performed to identify Acetylated H3.
  • ⁇ -SMA collagen I, PAI-1, E-cadherin, N-cadherin
  • western blot was performed to identify Acetylated H3.
  • the mouse tissue was ground to prepare a sample with protein.
  • SDS-PAGE was performed to transfer the fractionated proteins onto polyvinylidene difluoride membranes (PVDF) membranes.
  • PVDF polyvinylidene difluoride membranes
  • the protein-transported PVDF membrane was shaken and blocked for 1 hour in blocking buffer diluted with 5% skim milk in 1X TBST, and then the rabbit-derived polyclonal primary antibody was diluted 1000-fold in blocking buffer overnight. Reacted.
  • the membrane was washed with a buffer solution, and the secondary antibody against rabbits HRP conjugated was diluted 2000-fold in blocking buffer and reacted for 1 hour. After completion of the reaction, the membrane was washed with a buffer solution and reacted with the washed membrane by ECL.
  • Densitometry was measured by recording the mean value of two conts as 1 and recording the relative values. As a result, as shown in FIG. 5, the CG200745 concentration-dependent increase in histone acetylation and bleomycin treatment decreased the expression of fibrosis markers ( ⁇ -SMA, Collagen I, PAI-1).
  • the polyhexamethylene guanidine (PHMG) model was performed using 7-week-old C57BL / 6 female mice, and treated with polyhexamethyleneguanidine, polyhexamethyleneguanidine CG200745 15, 30, 60 mg / kg and 5 control groups. The experiment was divided into groups. The airways of the mice were dissected and 1 mg / kg polyhexamethyleneguanidine was injected into the airway at a volume of 50 ⁇ l. After injection, the incision site was closed with 5-0 nylon. Following polyhexamethyleneguanidine injection, drug administration was intraperitoneally administered for a total of two weeks.
  • mice After sacrifice, mice were thoracic and lungs were removed and fixed with 4% paraformaldehyde. After immersing in 4% paraformaldehyde for 48 hours and fixing at 4 °C, paraffin block was prepared and the paraffin embedding tissue was cut into 4 ⁇ m thickness and attached to the slide. Hemotoxiline & eosin staining and Masson's trichrome staining were performed.
  • Hemotoxiline & eosin staining was performed twice with slides of Xylene for 5 minutes, ethanol 100%, 95%, and 70% for 2 minutes, and washed in distilled water. After washing, the slides were soaked in hematoxylin for 1 minute, washed several times in flowing distilled water, and then immersed in eosin for 30 seconds and washed several times with flowing distilled water. Then, 1 minute each in 70%, 95% and 100% ethanol, and soaked 2 times in xylene for 2 minutes. Finally, the cover-slide was permanently attached using mounting medium xylene, and these samples were observed through an optical microscope.
  • Masson's trichrome staining was performed to stain collagen and muscle fibers. Slides were washed twice with xylene for 5 minutes each, twice with ethanol 100%, 95%, and 70%, and washed in distilled water. After washing, the slide was adjusted to 56 ⁇ 64 ° C. in a constant temperature water bath, and then reacted with Bouin's fluid for 1 hour and then cooled for 10 minutes. After washing several times in flowing distilled water, iron hematoxylin 5 minutes and rinsed in warm water for 2 minutes, then washed once more with distilled water. 5 minutes staining with Biebrich scarlet / Acid fuchsin solution and washing with distilled water.
  • the airway skin of the mouse was incised, the airways were exposed, 800 ⁇ l of PBS was put into the trachea, and 500 ⁇ l was recovered again to obtain a bronchoalveolar lavage fluid.
  • the bronchial alveolar lavage fluid was centrifuged at 4 ° C., 1,200 rpm for 5 minutes, and then the supernatant was obtained. 50 ⁇ l of bronchoalveolar lavage fluid and 1 ml of Sircol dye reagent were mixed for 30 minutes. After centrifugation at 4 ° C.
  • Tissue pulmonary fibrosis and related markers ( ⁇ -SMA, collagen I, PAI-1, E-cadherin, N-cadherin) and western blot were performed to identify Acetylated H3.
  • the mouse tissue was ground to prepare a sample with protein. After SDS-PAGE, the fractionated proteins were transferred to polyvinylidene difluoride membranes (PVDF) membrane.
  • PVDF polyvinylidene difluoride membranes
  • the protein-transported PVDF membrane was shaken and blocked for 1 hour in blocking buffer diluted with 5% skim milk in 1X TBST, and then the rabbit-derived polyclonal primary antibody was diluted 1000-fold in blocking buffer overnight. Reacted.
  • the membrane was washed with a buffer solution, and the secondary antibody against rabbits HRP conjugated was diluted 2000-fold in blocking buffer and reacted for 1 hour. After completion of the reaction, the membrane was washed with a buffer solution and reacted with the washed membrane by ECL.
  • Densitometry was measured by recording the mean value of two conts as 1 and recording the relative values. As a result, as shown in FIG. 8, the CG200745 concentration-dependent histone acetylation increase and polyhexamethyleneguanidine treatment increased the expression of fibrosis markers ( ⁇ -SMA, Collagen I, PAI-1).
  • the pulmonary fibrosis model is derived by one or more selected from the group consisting of bleomycin, polyhexamethyleneguanidine, chloromethylisothiazolinone, methylisothiazolinone, and ethoxyethylguadinin in addition to the components described above Applicable to

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du alkylcarbamoylnaphtalényloxyocténoylhydroxyamide, un dérivé de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, utilisé comme ingrédient efficace pour la prévention ou le traitement de la fibrose. En supprimant efficacement la prolifération des tissus fibreux, la composition peut être utilisée pour prévenir et/ou traiter la fibrose.
PCT/KR2019/003619 2018-03-28 2019-03-28 Composition pharmaceutique pour la prévention ou le traitement de la fibrose WO2019190214A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2020545550A JP2021516683A (ja) 2018-03-28 2019-03-28 線維症の予防または治療用の薬学組成物
RU2020132922A RU2020132922A (ru) 2018-03-28 2019-03-28 Фармацевтическая композиция для предупреждения или лечения фиброза
EP19774914.6A EP3777847A4 (fr) 2018-03-28 2019-03-28 Composition pharmaceutique pour la prévention ou le traitement de la fibrose
CN201980020179.8A CN111867571A (zh) 2018-03-28 2019-03-28 用于预防或治疗纤维化症的药学组合物
BR112020017776-8A BR112020017776A2 (pt) 2018-03-28 2019-03-28 Composição farmacêutica
US16/982,309 US20210015772A1 (en) 2018-03-28 2019-03-28 Pharmaceutical composition for prevention or treatment of fibrosis
CA3093779A CA3093779A1 (fr) 2018-03-28 2019-03-28 Composition pharmaceutique pour la prevention ou le traitement de la fibrose

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KR1020190034855A KR20190113639A (ko) 2018-03-28 2019-03-27 섬유화증 예방 또는 치료용 약학 조성물

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WO2011006040A2 (fr) * 2009-07-10 2011-01-13 Stowers Institute For Medical Research Procédés pour traiter une maladie rénale polykystique (pkd) ou d’autres maladies de formation de kystes

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