WO2025033596A1 - Composition pharmaceutique pour la prévention ou le traitement de maladies osseuses - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de maladies osseuses Download PDF

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WO2025033596A1
WO2025033596A1 PCT/KR2023/014722 KR2023014722W WO2025033596A1 WO 2025033596 A1 WO2025033596 A1 WO 2025033596A1 KR 2023014722 W KR2023014722 W KR 2023014722W WO 2025033596 A1 WO2025033596 A1 WO 2025033596A1
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bone
lsd1
chemical formula
osteoclast
protein
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Korean (ko)
Inventor
이태훈
조종현
이선우
김근중
김정선
김은애
최은랑
첸지하오
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Industry Foundation of Chonnam National University
Research Foundation for Industry Academy Cooperation of Dong A University
Chosun University Industry Academic Cooperation Foundation
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Industry Foundation of Chonnam National University
Research Foundation for Industry Academy Cooperation of Dong A University
Chosun University Industry Academic Cooperation Foundation
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Priority claimed from KR1020230104186A external-priority patent/KR102960952B1/ko
Application filed by Industry Foundation of Chonnam National University, Research Foundation for Industry Academy Cooperation of Dong A University, Chosun University Industry Academic Cooperation Foundation filed Critical Industry Foundation of Chonnam National University
Publication of WO2025033596A1 publication Critical patent/WO2025033596A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating bone disease.
  • Bone tissue is a tissue in which bone resorption by osteoclasts and bone formation by osteoblasts are continuously maintained. Osteoblasts are promoted to differentiate by signaling factors such as Bone Morphogenetic Protein 2 (BMP2). Osteoclast differentiation is promoted by the RANKL (Receptor Activator of Nuclear Factor Kappa- ⁇ Ligand) signaling substance produced during the osteoblast differentiation stage, and apoptosis occurs when differentiation is completed. Therefore, it is important that the differentiation and activity of osteoblasts and osteoclasts are harmoniously achieved during the normal bone regeneration process.
  • BMP2 Bone Morphogenetic Protein 2
  • osteoporosis When the balance between osteoblasts and osteoclasts is disrupted and bone absorption exceeds bone formation, the calcium in bone tissue decreases, bone density becomes thinner, and the medullary cavity widens. As the condition progresses, the bones become weaker and more prone to fracture even with small impacts. The disease caused by these symptoms is osteoporosis.
  • Osteoporosis is a condition in which bone matrix is pathologically thinned, bone density is reduced, bone strength is weakened, and the risk of fracture increases.
  • the strength of the skeleton is primarily formed and maintained by the bone matrix and the deposition of minerals within the bone matrix, which is clinically reflected in bone density. Osteoporosis is divided into primary osteoporosis and secondary osteoporosis depending on the cause.
  • Osteoclasts play a very important role in inducing bone resorption in bone diseases such as osteoporosis, periostitis, and rheumatoid arthritis. Therefore, many efforts have been made to find alternative drugs that can treat bone diseases by inhibiting osteoclast differentiation.
  • the present invention aims to provide a novel compound capable of inhibiting hyperdifferentiation of osteoclasts.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating bone disease.
  • the purpose of the present invention is to provide a health functional food for preventing or improving bone disease.
  • a pharmaceutical composition for preventing or treating bone disease comprising a compound represented by the following chemical formula 1:
  • the bone disease is any one selected from the group consisting of fracture, osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease, osteomalacia, osteopenia, bone atrophy, osteoarthritis, and avascular necrosis of the femur, a pharmaceutical composition for preventing or treating bone disease:
  • novel compound of the present invention and the pharmaceutical composition containing the same can exhibit excellent preventive or therapeutic effects on various bone diseases including osteoporosis by inhibiting osteoclast differentiation and/or production.
  • a health functional food containing the novel compound of the present invention can exhibit excellent preventive or improvement effects on various bone diseases, including osteoporosis, by inhibiting osteoclast differentiation and/or production.
  • FIGS 1a and 1b schematically illustrate the synthetic process of a TCP-(MP)-caffeic acid (Tranylcypromine-Methylpiperidine-Caffeic acid) analogue.
  • Figures 2a to 2g show the osteoclast formation inhibition effect (in vitro) of TCP-(MP)-caffeic acid analogues (CD-I-448 and 478) and three TCP-caffeic acid analogues (CD-I-389, CD-I-439, CD-I-442) corresponding to the chemical formula 1 compound of the present invention.
  • a and b are the results of fixing and staining mature osteoclasts using a Tartrate-Resistant Acid Phosphatase (TRAP) staining kit after culturing bone marrow-derived macrophages (BMDMs) in the induction medium supplemented with macrophage-colony stimulating factor (M-CSF) (30 ng/mL) and RANKL (50 ng/mL) for 4 days, and the result of calculating the area of TRAP-positive multinucleated osteoclasts (b).
  • M+R+D group treated with M-CSF, RANKL, and DMSO (Dimethyl sulfoxide) is the control group.
  • c is the result of in vitro LSD1 (Lysine-specific histone demethylase 1) activity assay.
  • CTRL DMSO treatment
  • d and e show the effect of CD-I-448 and CD-I-478, corresponding to compounds of formula 1, on protein methylation in bone-marrow derived macrophages (BMDMs) using an LSD1 activity x-in vivo assay.
  • MR ((M-CSF and RANKL treated group) and GSK-LSD1 (GSK-LSD1 Dihydrochloride treated group) are controls.
  • f and g are the results of staining cells using an alkaline phosphatase (ALP staining) assay kit after primary calvarial cells were treated with BMP2 (100 ng/mL) and cultured with DMSO or labeled novel LSD1 inhibitors (2 ⁇ M) for 9 days (f) and the ALP positivity density (%) (g) indicating osteoblast differentiation measured by Image J.
  • BMP2 is the control.
  • the data reflect the results of three independent experiments (scale bar: 100 ⁇ m. * p ⁇ 0.05 and ** p ⁇ 0.05 vs. DMSO control).
  • Figures 3a to 3h show the dose-dependent osteoclast formation inhibitory effects (in vitro) of TCP-(MP)-caffeic acid analogues.
  • a to d show the results of fixing the formed mature osteoclasts and staining them using a TRAP staining kit after culturing BMDMs for 4 days in the induction medium supplied with M-CSF (30 ng/mL) and RANKL (50 ng/mL) with or without the indicated doses of CD-I-448 (a), and calculating the area of TRAP-positive multinucleated osteoclasts (b), the number of cells by nuclear type (c), and the total number of cells per well (d).
  • MR the group treated with M-CSF and RANKL
  • e to g show the osteoclast bone resorption assay effect (in vitro) to evaluate the effect of CD-I-448 (e), the result of supernatant fluorescence analysis of the indicated groups (f), and the result of calculating the resorbed pore area (%) (g) of the indicated groups using Image J software.
  • MR M-CSF and RANKL-treated group
  • h shows the results of cell viability assay of CD-I-448 at the indicated doses. Data are representative of at least three independent experiments. (Scale bar: 200 ⁇ m. 0 ⁇ M - control group vs. MR (M-CSF and RANKL-treated group) * p ⁇ 0.05, ** p ⁇ 0.01, and *** p ⁇ 0.001; G indicates GSK-LSD1.)
  • Figure 4a and b show that CD-I-448 inhibits the formation of F-actin belts (in vitro).
  • a shows the results of F-actin staining analysis to evaluate the effect of CD-I-448 on RANKL-induced F-actin belt formation.
  • b shows the results of calculating the size (%) of the F-actin ring in the indicated groups using Image J.
  • CTRL M-CSF + RANKL treatment group
  • Figure 5a and b show that CD-I-478 inhibits osteoclast bone resorption (in vitro).
  • a shows the results of a bone resorption assay performed to evaluate the extent of osteoclast bone resorption according to the difference in the indicated dose of CD-I-478.
  • b shows the results of calculating the resorption pit area (%) of the indicated groups using Image J.
  • MR the group treated with M-CSF and RANKL
  • Figures 6a to 6f show the preventive effects of CDI-448 on bone loss in ovariectomized rat (OVX)-induced osteoporotic mice.
  • b and c represent the measured and calculated bone mineral density (BMD), bone surface (BS), trabecular volume (Tb-V), and total volume (TV) of each sample.
  • d represents the mouse body weights of each group for in vivo analysis.
  • e histological evaluation of the effects of CDI-448 (5 or 10 mg/kg) on OVX-induced bone loss and representative images of demineralized bone stained with TRAP and H&E (hematoxylin and eosin).
  • FIG. 7 shows the results of purifying the LSD1/CoREST (Corepressor for RE1-Silencing Transcription factor) complex.
  • Figures 8a to 8f show the results of confirming the interaction of CD-I-448 and CD-I-478 with the LSD1/CoREST complex, and showing the structure of CD-I-478 within the LSD1/CoREST complex.
  • a and b show the results of SPR (Surface Plasmon Resonance) analysis of CD-I-448 and CD-I-478 and the LSD1/CoREST complex.
  • c shows the result of ITC (Isothermal Titration Calorimetry) analysis of CD-I-478 and the LSD1/CoREST complex.
  • d shows the crystal structure of the complexed LSD1/CoREST, and the two protein chains of LSD1 and CoREST are represented as ribbons and are distinguished by color (LSD1 is green, CoREST is turquoise).
  • LSD1 is green
  • CoREST is turquoise
  • the cylinder and the arrow represent an alpha-helix and a beta-strand, respectively.
  • the FAD cofactor within the active site of LSD1 was derived from CD-1-478, as magnified in the lower left panel. It is represented as a stick model in different atomic colors in the 2Fo-Fc electron density, with yellow contour lines at the 1.5 s level.
  • e is shown for comparison of inhibitors bound to the active site of LSD1. Inhibitors bound to protein backbones are indicated in different colors.
  • Figures 9a to h show the results of SPR and differential scanning fluorimetry (DSF) analyses of TCP-(MP)-caffeic acid analogues using the LSD1/CoREST complex.
  • SPR kinetics analyses of GSK-LSD1 and GSK2879552 (a and b), and DSF analyses of GSK2879552, CD-I-448, and CD-I-478 (c to h) are shown.
  • Figures 10a to 10d show that CD-I-448 is converted to CD-I-478 by releasing TBS (t-butyldimethylsilyl) and the like.
  • Blank rat plasma (a), CD-I-448 in mouse plasma (b), CD-I-478 in mouse plasma (c), and mouse plasma after intravenous injection of CD-I-448 (d) are shown.
  • Samples (b) and (c) were prepared at a concentration of 5 ⁇ g/ml and incubated in rat plasma for 0.5 h, and the plasma sample (d) was obtained 5 minutes after intravenous administration at a dose of 20 mg/kg, and the chromatogram of each sample represents the results measured using mass spectrometry.
  • Figures 11a to g show the effect of CDI-448 on inhibiting the expression of osteoclast-specific genes and proteins.
  • a to f show the effect of CDI-448 on inhibiting the expression of osteoclast-specific markers induced through RANKL.
  • the black bar represents the control group (Con), and the gray bar represents the CD-I-448 treatment group.
  • Transcript levels are normalized to the expression of the control group on day 0.
  • g indicates that CD-I-448 inhibits the expression of key osteoclast proteins induced by RANKL, such as NFATc1, c-fos, and Ctsk.
  • ⁇ -Actin is shown as a loading control. (* p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001 vs. vehicle-treated “Con” (0 ⁇ M).)
  • Figure 12a to d show that BMDMs were cultured with or without 2 ⁇ M of CD-I-448 or CD-I-448+MG132 (Z-Leu-leu-leu-al), and that 10 ⁇ M MG132 was treated for the last 6 hours, and then the protein expression of NFATc1 was analyzed (a).
  • b shows that the protein expression of CtsK, an osteoclast maturation-specific protein, was analyzed, and the expression of CBL (Casitas B-lineage Lymphoma), p-LSD1, and methyl lysine was analyzed for 0, 1, 2, and 4 days.
  • c shows that the lysine methylation of CBL protein was analyzed in the indicated groups, and the interaction of CBL with p-LSD1 and NFATc1 was analyzed.
  • CBL protein was used as an input control.
  • d shows the effect of CD-I-448 and GSK-LSD1 at the indicated doses on NFATc1 lysine 48-linked Ub. (0 ⁇ M - treated as “Con”, “M” indicates ‘M-CSF’.)
  • Figures 13a and b show the results of CO-IP analysis (a) to examine CBL methylation via IP methyl lysine and Western blot CBL, and the results of CO-IP analysis (b) to confirm the interaction of p-LSD1 and CBL via IP p-LSD1 and Western blot CBL.
  • Figure 14 shows a mechanism diagram of a proposed TCP-(MP)-caffeic acid analogue in the treatment of osteoclast bone loss. (Created with BioRender.com)
  • the present invention relates to a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; and uses thereof.
  • the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:
  • R is hydrogen or t-butyldimethylsilyl (TBS).
  • the compound represented by chemical formula 1 is a compound represented by chemical formula 2 or chemical formula 3 below.
  • the compound represented by chemical formula 1 and a pharmaceutically acceptable salt thereof can exhibit an effect of inhibiting osteoclast differentiation. More specifically, the compound represented by chemical formula 1 and a pharmaceutically acceptable salt thereof can inhibit the demethylation activity of LSD1 and stabilize the CBL protein by reducing the direct interaction between LSD1 and CBL, thereby inhibiting osteoclast differentiation.
  • osteoclast bone loss was inhibited after treatment with CD-I-448 corresponding to the compound of chemical formula 1 in an OVX-induced osteoporosis mouse model.
  • the present invention provides a pharmaceutical composition for preventing or treating bone disease, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:
  • R is hydrogen or t-butyldimethylsilyl (TBS).
  • pharmaceutically acceptable means that the compound or composition exhibits the property of not causing significant irritation to the subject, cell, tissue, etc. to which it is administered and does not impair the biological activity and physical properties of the compound.
  • Pharmaceutically acceptable salts can be, for example, acid addition salts, base addition salts or metal salts.
  • Acid addition salts can be formed from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous or phosphorous acid
  • non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propylates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoate, dinitrobenzoate, hydroxybenzoates, methoxybenzoates, phthalates, terephthalate, benzenesulfonate
  • an acid addition salt of a compound represented by formula 1 can be obtained by dissolving the compound in an excess aqueous acid solution and precipitating the salt using a hydratable organic solvent, such as methanol, ethanol, acetone or acetonitrile.
  • a hydratable organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • the metal salt may be a sodium, potassium or calcium salt.
  • the metal salt may be prepared using a base, for example, an alkali metal or alkaline earth metal salt may be obtained by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering off the undissolved compound salt and evaporating and/or drying the filtrate.
  • the bone disease that can be prevented or treated by the pharmaceutical composition of the present invention may be caused by an imbalance in the activity of osteoblasts and osteoclasts, and more specifically, the bone disease may be caused by osteoclast hyperdifferentiation or decreased osteoblast activity.
  • osteoclasts When osteoclasts become overdifferentiated, they may increase abnormally, resulting in excessive bone resorption, which may lower bone density and cause various diseases such as osteoporosis, osteomalacia, osteopenia, bone atrophy, and periodontitis.
  • the above bone disease may be, but is not limited to, a fracture, osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease, osteomalacia, osteopenia, osteoatrophy, osteoarthritis or avascular necrosis of the femur, bone loss, an osteoporotic fracture, a diabetic fracture, a nonunion fracture, osteogenesis imperfecta, an osteomalacia fracture, an osteogenesis disorder, a degenerative bone disease, a malocclusion, a bone union disorder, pseudarthrosis, osteonecrosis, osteoarthritis, a bone tumor, a bone cancer, and the like.
  • the bone disease may be any one selected from the group consisting of a fracture, osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease, osteomalacia, osteopenia, osteoatrophy, osteoarthritis, and avascular necrosis of the femur.
  • Periodontitis is an inflammatory response caused by the immune cell defense against periapical bacterial infection.
  • Neutrophils which are mainly involved in periodontitis, secrete prostaglandins, which are inflammatory mediators.
  • Osteoclasts which absorb bone tissue, are activated by cell signaling substances such as prostaglandins, and alveolar bone loss is observed around the inflamed area.
  • chronic periodontitis shows continuous inflammation and alveolar bone erosion of the periodontal apex, and when periodontitis worsens and the tooth cannot be saved, the tooth is extracted and an implant is performed.
  • the pharmaceutical composition of the present invention can be used to prevent or treat periodontitis by inhibiting the differentiation of osteoclasts and preventing bone absorption.
  • prevention includes any action that inhibits or delays the onset of a bone disease.
  • treatment includes any action that improves or beneficially alters the symptoms of a subject with a bone disease.
  • the pharmaceutical composition of the present invention may be administered in combination with known substances for the prevention or treatment of bone diseases.
  • the pharmaceutical composition of the present invention may be administered in combination with cinchonine, brown worm extract, aloe-imodin, and omega-3 fatty acids, arteannuin B, indole-2-carboxylate derivatives, euphobia factor L1, skullcapflavone derivatives, and fraxinelone.
  • administration means introducing a given substance into a subject by an appropriate method
  • subject means any animal, including humans, rats, mice, livestock, etc., that has developed or can develop a bone disease.
  • subject means any animal, including humans, rats, mice, livestock, etc., that has developed or can develop a bone disease.
  • a specific example may be a mammal, including humans.
  • the pharmaceutical composition of the present invention may be in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage.
  • the pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, as well as external preparations, suppositories, and injections.
  • the pharmaceutical composition of the present invention may contain the active ingredient alone, or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment, a fragrance, etc. for oral administration, and may be used in combination with a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. for injections, and may be used in combination with a base, an excipient, a lubricant, a preservative, etc. for topical administration.
  • the formulation of the pharmaceutical composition of the present invention can be variously manufactured by mixing it with a pharmaceutically acceptable carrier, and for example, in the case of oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be manufactured in the form of unit dose ampoules or multiple doses.
  • the formulation of the pharmaceutical composition of the present invention can be manufactured in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.
  • Carriers, excipients and diluents for formulation may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, fillers, anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers or preservatives.
  • the route of administration of the pharmaceutical composition of the present invention may be oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal, but is not limited thereto.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, the injection method can be selected from external application to the skin, intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the degree of the disease, the drug form, the route of administration, and the period of administration, but can be appropriately selected by a person skilled in the art.
  • the pharmaceutical composition of the present invention may be administered at 0.0001 mg to 1000 mg/kg or 0.001 mg to 500 mg/kg per day.
  • the pharmaceutical composition of the present invention may be administered once a day or divided into several doses.
  • the present invention provides a health functional food for improving bone health, comprising a compound represented by the following chemical formula 1 or a food-wise acceptable salt thereof:
  • R is hydrogen or t-butyldimethylsilyl (TBS).
  • improving bone health includes all effects that ensure that the balance between bone breakdown and remodeling is maintained.
  • the health functional food of the present invention can improve bone health by helping to maintain the balance between bone decomposition and bone remodeling.
  • Health functional foods refer to foods manufactured and processed using raw materials or ingredients with functionality useful to the human body according to the Health Functional Food Act, and the functionality may mean consumption for the purpose of obtaining useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological effects.
  • a health functional food may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, further including one or more of a carrier, diluent, excipient, and additive.
  • Health functional foods can be, for example, various foods, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, or health functional foods.
  • Additives that may be included in health functional foods may be selected from the group consisting of natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, antioxidants, glycerin, alcohol, carbonating agents, and fruit pulp.
  • natural carbohydrates flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, antioxidants, glycerin, alcohol, carbonating agents, and fruit pulp.
  • Natural carbohydrates include, for example, monosaccharides, such as glucose, fructose, etc.; disaccharides, such as maltose, sucrose, etc.; and polysaccharides, such as dextrin, cyclodextrin, etc., common sugars, and sugar alcohols, such as xylitol, sorbitol, erythritol, etc.
  • sweetening agents thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • Health functional foods may further include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and fruit pulp for the production of natural fruit juice and vegetable beverages.
  • flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.
  • pectic acid and its salts such as synthetic flavoring agents and
  • Carriers, excipients, diluents and additives may be selected from the group consisting of, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.
  • the health functional food of the present invention can be prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.
  • TCP-(MP)-caffeic acid analogues CD-I-448 (compound 12 below) and 478 (compound 13 below)
  • TCP-caffeic acid analogues CD-I-389 (compound 6 below), CD-I-439 (compound 7 below), CD-I-442 (compound 9 below)
  • CD-I-389 compound 6 below
  • CD-I-439 compound 7 below
  • CD-I-442 compound 9 below
  • (B) a) (i) TBDMSCl, DIEA, CH 2 Cl 2 , 25 °C, 14 h; (ii) K 2 CO 3 , THF/H 2 O(5:1 v/v), room temperature, 2 h; b) TMSCl, Et 3 N, CH 2 Cl 2 , from 0 °C to room temperature, 3 h; c) EDC HCl, HOBt H 2 O, DIEA, CH 2 Cl 2 , room temperature, 12 h; d) (i) Dess-Martin periodinane, CH2Cl2 , 0°C to room temperature, 3 hours; (ii) TCP ⁇ HCl( 3 ), NaBH(OAc) 3 , DCE, 0°C to room temperature, 12 hours; e) 6N HCl propanol solution, MeOH, 0°C, 3 hours
  • Trans-( ⁇ )-tranylcypromine-hydrochloride (trans-( ⁇ )-TCP-HCl) (3) and caffeic acid (4) were prepared in four steps to produce trans-( ⁇ )-tranylcypromine-caffeic acid analogue (TCP-CA, 7) and TCP-3,4,5-trimethoxy cinnamic acid derivative ( 9 ).
  • Step 2 4-(( E )-3-oxo-3-(((1S,2R)-2-phenylcyclopropyl)amino)prop-1-en-1-yl)-1,2-phenylene diacetate (diacylated TCP-CA derivative) (6) Preparation
  • Step 3 ( E )-3-(3,4-dihydroxyphenyl) -N -((1S , 2R ) -2-Phenylcyclopropyl)acrylamide (TCP-caffeic acid) (7) manufacturing
  • TCP-MP-CA (13) was prepared as an analogue of GSK-2879552 (TCP-MP-BzOH structure) through five steps from trans-( ⁇ )-TCP-HCl (TCP-HCl) (3).
  • Step 1 ( E )-3-(3,4-bis((tyr-butyldimethylsilyl)oxy)phenyl)acrylic acid (non-silylated caffeic acid derivative)(10) Preparation
  • Step 4 ( E Preparation of )-3-(3,4-bis((tyr-butyldimethylsilyl)oxy)phenyl)-1-(4-(((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperiden-1-yl)prop-2-en-1-one (disilylated TCP-MP-CA derivative)(12)
  • the concentrate was dissolved in 6.5 mL of anhydrous DCE and treated with tranylcypromine hydrochloride (0.6 g, 3.56 mmol) and sodium triacetoxyborohydride (1.5 g, 7.12 mmol) at 0°C.
  • the reaction solution was stirred at room temperature for 12 h and then poured into ice-ether (1:1 v/v).
  • the organic layer was separated and washed with saturated NaHCO 3 (10 mL).
  • the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • GSK-LSD1 Dihydrochloride (PubChem CID: 91663353, molecular formula: C 14 H 22 Cl 2 N 2 , molecular weight: 289.24) was purchased from MedChemExpress and dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich).
  • Fetal bovine serum (FBS) and alpha modified Eagle's minimal essential medium ( ⁇ -MEM) were purchased from Thermo Fisher Scientific.
  • Mouse M-CSF and RANKL were purchased from PeproTech.
  • Anti- ⁇ -actin (A5441) from Sigma-Aldrich; Anti-cathepsin K (sc-48353), anti-cbl (sc-1651); anti-K48-linked specific polyubiquitin (8081s), anti-c-fos (4384s), anti-NFATc1 (8032s), and secondary antibodies (7074s and 7076s) were purchased from Santa Cruz Biotechnology.
  • Anti-Methyl-Lysine (nb500-824) was purchased from Novus, and anti-p-LSD1 (ABE1462) was purchased from Merck Millipore.
  • the ECL system for chemiluminescence signal detection (RPN2106) was purchased from iNtRON. Tartrate-resistant acid phosphatase staining kit was purchased from CosmoBio.
  • Bone marrow cells from 8-week-old C57/BL6 female mice were isolated by rinsing or washing the femurs and tibias with ⁇ -MEM. Then, BMCs were cultured in ⁇ -MEM containing 10% FBS, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin at 37°C in a 5% CO 2 incubator for 24–36 h. Supernatant cells were collected and cultured for 3 days while supplying 30 ng/mL M-CSF. Adherent cells were then collected and used as BMDMs for osteoclast induction. All experiments using animals were approved by the Chonnam National University IACUC (Approval Number: CNU IACUC-YB-2022-123).
  • adherent cells were harvested and cultured in ⁇ -MEM containing 10% FBS, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, 30 ng/mL M-CSF, and 50 ng/mL RANKL with or without TCP-(MP)-caffeic acid analogues for about 4 days.
  • ⁇ -MEM containing 10% FBS, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, 30 ng/mL M-CSF, and 50 ng/mL RANKL with or without TCP-(MP)-caffeic acid analogues for about 4 days.
  • all osteoclasts were fixed using 4% formalin for about 20 min.
  • the cells were stained using a TRAP staining kit.
  • the spread osteoclast area was visualized using a microscope and calculated using imageJ.
  • the viability of BMDM (1 ⁇ 104 cells/well) was assessed in 96-well plates using a cell viability as
  • Bone resorption assays were performed as previously described. BMDMs at 2 ⁇ 104 cells/well were cultured in coated 48-well plates provided in the kit (CSR-BRA-48X2KIT). They were then cultured with or without the indicated doses of CD-I-448 and CD-I-478 until mature osteoclasts were observed. 100 ⁇ L of supernatant per well was collected into a black polypropylene 96-well microplate, and fluorescence intensity was measured at an excitation wavelength of 485 nm and an emission wavelength of 535 nm using a SpectraMax i3x fluorescence plate reader. Resorbed pit areas were visualized using a microscope and calculated by ImageJ. For F-actin ring analysis, belts were visually identified using a rhodamine-conjugated phalloidin staining kit (abcam) as previously described.
  • abcam rhodamine-conjugated phalloidin staining kit
  • the mouse GAPDH (glyceraldehyde-3-phosphate dehydrogenase) gene was used as a reference gene.
  • the primers used are as shown in Table 1 below.
  • Total protein was extracted from osteoclasts treated or not with CD-I-448 using cold RIPA buffer on ice for 30 min. After quantifying the protein concentration with a gold BCA protein assay kit, the proteins were loaded and separated using 8% or 12% SDS-PAGE. They were then transferred to polyvinylidene fluoride (PVDF) membranes. Next, the PVDF membranes were blocked with 5% skim milk for 1 h, excised based on the molecular weight of the target proteins, and incubated overnight with primary antibodies diluted 1:2,000 times. They were washed with 1 ⁇ TBST and reacted with secondary antibodies diluted 1:2,000 times for 2 h at room temperature (RT). Finally, the membranes were washed and developed using Super Plus chemiluminescence (ECL) buffer for exposure and imaging.
  • ECL Super Plus chemiluminescence
  • TCP-(MP)-caffeic acid analogues were assayed using the LSD1 inhibitor screening kit according to the manufacturer's instructions (Caymanchem, Michigan, USA).
  • the mixture sample, assay buffer, LSD1 human recombinant assay reagent, LSD1 assay fluorometric substrate, LSD1 assay horseradish peroxidase, and LSD1 assay peptide were added to a 96-well plate (black). Background wells were not supplemented with LSD1 assay peptide, and the LSD1 assay peptide group used as the initial activity and the inhibitor were not added.
  • mice in the OVX, CD-I-448, and GSK-LSD1 groups underwent OVX surgery.
  • the control group underwent abdominal incision.
  • the CD-I-448 and GSK-LSD1 groups received intraperitoneal injections of 5 or 10 mg/kg dissolved in a mixture of 10% Tween 80 and 10% DMSO.
  • Mice in the Sham and OVX groups were administered the same volume of a mixture of 10% Tween 80 and 10% DMSO by intraperitoneal injection every day.
  • the injection volume was 200 ⁇ L per mouse, and the treatment was conducted for 4 weeks.
  • the body weights of the mice were measured weekly.
  • the mice were euthanized, and the femurs were separated, fixed with 4.0% paraformaldehyde, and then used for micro-computed tomography (micro-CT) analysis.
  • micro-CT micro-computed tomography
  • Sprague-Dawley mice male, 6-7 weeks old, weighing 200-230 g were purchased from Orient Bio (Seongnam, Korea). All animal experiments were approved by the Kmedihub Animal Care and Use Committee and performed in accordance with the Kmedihub guidelines for the welfare and ethics of laboratory animals. Chromatographic analysis of plasma samples for CD-I-448 was performed by LC-MS/MS at the Kmedihub Preclinical Research Center. Chromatograms collected at different time points were analyzed by LC-MS/MS scanning method using an Agilent 6400 triple quadrupole instrument (Agilent Technologies, Waldbronn, Germany).
  • the mobile phase was acetonitrile:water (80:20) containing ammonium formate, and the flow rate was set at 0.2 ml/min.
  • the column effluent was monitored by a mass spectrometer equipped with ESI in positive ion mode.
  • the purified protein was concentrated to 8 mg mL -1 in a buffer consisting of 20 mM Tris-HCl (pH 7.5), 200 mM NaCl, and 10 mM mercaptoethanol for crystallization.
  • concentration of the purified LSD1/CoREST protein complex was determined using absorbance measurements at 280 nm and the theoretical extinction coefficient at 280 nm.
  • the purified LSD1/CoREST was crystallized using the hanging-drop vapor-diffusion method in VDX plates (Hampton Research). A protein solution (1 ⁇ L) at a concentration of 8 mg mL -1 was mixed with an equal volume of reservoir solution at 295 K.
  • the structure was determined to a resolution of 3.5 ⁇ using the molecular replacement method in the PHENIX package, using the human LSD1/CoREST complex (PDB ID 6K3E) as a search model.
  • PDB ID 6K3E human LSD1/CoREST complex
  • One copy of the LSD1 and CoREST complexes in the asymmetric unit was identified, refined using the PHENIX package, and then manually rebuilt.
  • the final model was obtained at a resolution of 3.0 ⁇ after iterative manual model building and refinement with the Coot17 and PHENIX packages, respectively.
  • Molecular model figures were prepared using the PyMol molecular graphics program (Schr ⁇ dinger, LLC).
  • Micro-CT scanning was performed using the Quantum GX Micro-CT imaging system at the Korea Basic Science Institute (Gwangju, Korea).
  • CD-I-448 corresponding to the compound RANKL-induced osteoclast differentiation, F-actin belt formation and bone resorption inhibition effect (in vitro)
  • TRAP staining (a specific characteristic of osteoclasts) analysis was adopted to confirm the inhibitory effect of CD-I-448 on RANKL-induced osteoclast formation in the indicated concentration range (Fig. 3a to d).
  • Fig. 3a to h the differentiation of BMDM was significantly inhibited by CD-I-448.
  • rhodamine-labeled phalloidin was used to mark the formed F-actin belt of mature osteoclasts, as shown in Fig. 4a and b, the control group (CTRL) had well formed rings, while CD-I-448 inhibited the formation of F-actin rings at 1 ⁇ M CD-I-448.
  • Bone resorption is an important function of osteoclasts in the bone remodeling process. Therefore, the osteoclast bone resorption inhibition ability of CD-I-448 was assayed in vitro using a fluoresceinamine-labeled calcium phosphate plate. As shown in Fig. 3 e to g, obvious bone resorption pits were observed in the group treated with M-CSF and RANKL (MR group); the resorption pit area was significantly reduced by CD-I-448 treatment (1, 2, and 4 ⁇ M). In addition, Fig. 3 f and g confirmed that CD-I-448 reduced the fluorescence intensity and pit area formation in a dose-dependent manner (GSK-LSD1 (G) was used as a control inhibitor).
  • CD-I-478 significantly inhibited osteoclast bone resorption in vitro (Fig. 5 a and b).
  • CD-I-448 did not significantly affect the cell viability of BMDMs at least below 10 ⁇ M, whereas it completely blocked the formation of multinucleated mature osteoclasts when treated at 4 ⁇ M (Fig. 3a and b). This indicates that CD-I-448 dose-dependently inhibits RANKL-mediated osteoclast formation.
  • CD-I-448 could significantly inhibit RANKL-mediated osteoclast differentiation and osteoclast-related bone resorption activity by reducing the formation of osteoclasts.
  • the compound of formula 1 was confirmed to inhibit osteoclast differentiation, F-actin belt formation, and bone resorption induced by RANKL.
  • CD-I-448 As shown in Figures 8a and b, the results confirmed that both CD-I-448 and CD-I-478 directly bound to the LSD1/CoREST complex. In addition, since we found that CD-I-448 would soon be converted to CD-I-478 and function ( Figure 10a to d), CD-I-478 was selected for isothermal calorimetric titration (ICT) analysis and crystal structure analysis using LSD1/CoREST ( Figure 8c to f). The ICT curves of 50 ⁇ M LSD1-CoREST and 500 ⁇ M CD-I-478 at 20 °C are shown in Figure 8c. The upper panel shows the raw ITC data.
  • ICT isothermal calorimetric titration
  • the lower panel shows the integrated heat per injection (solid circles) corrected for background plotted for the injection of CD-I-478 into LSD1/CoREST.
  • the solid line is a fit to a single-site independent binding model, which yielded a stoichiometry of 1.1, a molar enthalpy change ( ⁇ H) of -20.44 kJ mol-1, and a binding affinity (Kd) of 2.331 ⁇ 10 -7 M (Fig. 8c).
  • ⁇ H molar enthalpy change
  • Kd binding affinity
  • the solved structure shows an adduct that is continuous with the flavin ring of flavin adenine dinucleotide but does not allow for the full chemistry of CD-I-478 (Fig. 8d). Instead, the adduct may be slightly larger than the phenyl ring that is part of CD-I-478.
  • the adduct may be slightly larger than the phenyl ring that is part of CD-I-478.
  • no extra bulky electron density is observed for the entire chemical entity, suggesting that the highly active cyclopropyl ring of the inhibitor opens to form an extra five-membered ring with the flavin ring atom of FAD.
  • This kind of covalent bond formation with the N5 atom of the flavin ring has been reported for several LSD1 inhibitors (Fig. 8e).
  • CD-I-448 inhibited osteoclastogenesis (in vitro) and osteoclast bone loss (in vivo) (Figs. 3a to h, 4a and b).
  • CD-I-448 directly targeted the LSD1/CoREST complex to reduce its demethylation activity during osteoclastogenesis (Figs. 8a to f, 2c and d).
  • LSD1 demethylation activity by CD-I-448 blocks osteoclastogenesis.
  • the lysine methylation of CBL after CD-I-448 treatment during osteoclastogenesis was increased after TCP-(MP)-caffeic acid analogue treatment compared to the control group (Con group), and GSK-LSD1 (a popular LSD1 inhibitor) was used as a control.
  • the interaction between p-LSD1 and CBL was reduced (convert CO-IP analysis is shown in a and b of Fig. 13).
  • the interaction of CBL and NFATc1 protein increased with the treatment of TCP-(MP)-caffeic acid analogue.
  • CBL protein is an E3 ligase that mediates protein degradation through lysine 48-linked ubiquitination. Therefore, we analyzed the level of lysine 48-linked ubiquitination protein of NFATc1 according to the presence or absence of CD-I-448 treatment (Fig. 12d). GSK-LSD1 was used as a control inhibitor for LSD1 inhibition.
  • lysine 48 ubiquitination of NFATc1 significantly increased after treatment with TCP-(MP)-caffeic acid analogues compared to the control group (Con group), confirming that CD-I-448 inhibits osteoclastogenesis induced by RANKL by increasing the degradation of NFATc1 protein through lysine 48 ubiquitination.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter des maladies osseuses, et comprenant plus spécifiquement un analogue d'acide caféique TCP-(MP), pouvant ainsi inhiber la différenciation et/ou la génération d'ostéoclastes et présenter un excellent effet de prévention ou de traitement sur diverses maladies osseuses, y compris l'ostéoporose et analogues.
PCT/KR2023/014722 2023-08-09 2023-09-26 Composition pharmaceutique pour la prévention ou le traitement de maladies osseuses Pending WO2025033596A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180051523A (ko) * 2015-08-12 2018-05-16 인사이트 코포레이션 Lsd1 저해제의 염
WO2018091691A1 (fr) * 2016-11-17 2018-05-24 Cytoo Inhibiteurs de lsd1 en tant qu'inducteurs d'hypertrophie du muscle squelettique
KR20180117602A (ko) * 2015-12-29 2018-10-29 미라티 테라퓨틱스, 인크. Lsd1 억제제
KR20180134675A (ko) * 2017-06-09 2018-12-19 한미약품 주식회사 시클로프로필아민 유도체 화합물 및 이의 용도

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180051523A (ko) * 2015-08-12 2018-05-16 인사이트 코포레이션 Lsd1 저해제의 염
KR20180117602A (ko) * 2015-12-29 2018-10-29 미라티 테라퓨틱스, 인크. Lsd1 억제제
WO2018091691A1 (fr) * 2016-11-17 2018-05-24 Cytoo Inhibiteurs de lsd1 en tant qu'inducteurs d'hypertrophie du muscle squelettique
KR20180134675A (ko) * 2017-06-09 2018-12-19 한미약품 주식회사 시클로프로필아민 유도체 화합물 및 이의 용도

Non-Patent Citations (1)

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Title
DING MINA, CHEN ZHIHAO, CHO EUNJIN, PARK SANG-WOOK, LEE TAE-HOON: "Crucial Role of Lysine-Specific Histone Demethylase 1 in RANKL-Mediated Osteoclast Differentiation", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 24, no. 4, CH, pages 3605 - 3605-16, XP093275524, ISSN: 1422-0067, DOI: 10.3390/ijms24043605 *

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