WO2024085557A1 - Composition destinée à la prévention ou au traitement de maladies induites par oscar, comprenant de l'adéfovir en tant que principe actif - Google Patents

Composition destinée à la prévention ou au traitement de maladies induites par oscar, comprenant de l'adéfovir en tant que principe actif Download PDF

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WO2024085557A1
WO2024085557A1 PCT/KR2023/015908 KR2023015908W WO2024085557A1 WO 2024085557 A1 WO2024085557 A1 WO 2024085557A1 KR 2023015908 W KR2023015908 W KR 2023015908W WO 2024085557 A1 WO2024085557 A1 WO 2024085557A1
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oscar
adefovir
composition
pharmaceutical composition
cartilage
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PCT/KR2023/015908
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English (en)
Korean (ko)
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김완규
박세라
이수영
김지희
Original Assignee
주식회사 카이팜
이화여자대학교 산학협력단
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Publication of WO2024085557A1 publication Critical patent/WO2024085557A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a composition for preventing or treating osteoclast-associated Ig-like receptor (OSCAR)-induced diseases containing adefovir as an active ingredient.
  • OSCAR osteoclast-associated Ig-like receptor
  • OSCAR osteoclast-associated Ig-like receptor
  • OSCAR is a cell surface receptor with two immunoglobulin domains that belongs to the leukocyte receptor complex.
  • Oscar regulates osteoclast differentiation through osteoclast-specific expression. This differentiation of osteoclasts is regulated through the interaction between osteoclasts and osteoblasts. During this process, osteoblasts secrete collagen outside the cells, and the secreted collagen functions as a ligand for Oscar.
  • substances that have the activity of inhibiting the mutual binding of collagen and Oscar can inhibit the activity of Oscar. These substances can be used as inhibitors of diseases induced by collagen-Oscar binding.
  • OSCAR-induced diseases include various cancers including bladder cancer, breast cancer, cholangiocarcinoma, colon adenocarcinoma, esophageal cancer, head and neck cancer, renal induced cell carcinoma, rectal adenocarcinoma, gastric adenocarcinoma, and thyroid carcinoma, hypertension, periodontal disease, and bone cancer.
  • Metabolic diseases, rheumatoid arthritis, chronic obstructive pulmonary disease, emphysema, pneumonia, tuberculosis, cardiovascular diseases, atherosclerosis, diabetes, etc. are known.
  • OSCAR is highly expressed in the above diseases, and OSCAR levels are associated with the severity of the disease.
  • Adefovir is useful as an antiviral treatment and can be formulated as adefovir depivoxil.
  • Adefovir has the structural formula of Formula 1, and its compound name is 9-(2-(phosphonomethoxy)ethyl)adenine (PMEA).
  • Adefovir dipivoxil is a prodrug of adefovir developed to improve the low oral absorption rate of adefovir.
  • Adefovir dipivoxil has the structural formula of Formula 2, and its compound name is [2-[bis(pivaloyloxy)methoxyphosphi. It is nylmethoxy]ethyl]adenine (bis-POM PMEA).
  • Adefovir dipivoxil is a nucleotide reverse transcriptase inhibitor that shows excellent therapeutic effects against hepatitis B and HIV, and is sold under the trade name Hepsera.
  • the present inventors studied compounds that inhibit or bind to Oscar based on artificial intelligence or big data analysis, which are drug information search methods based on compound activity data. As a result, adefovir controls Oscar signaling and OSCAR mRNA expression.
  • the present invention was completed by confirming the treatment effect of OSCAR-induced diseases, including bone metabolic diseases, by alleviating inflammation and promoting differentiation and regeneration of chondrocytes as an OSCAR inhibitor that reduces .
  • the object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of osteoclast-associated Ig-like receptor (OSCAR)-induced diseases, comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient. It is provided.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide a method of treating OSCAR-induced disease, comprising administering the pharmaceutical composition to a subject suspected of having OSCAR (osteoclast-associated Ig-like receptor; OSCAR)-induced disease.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide the use of adefovir, a pharmaceutically acceptable salt or prodrug thereof for the prevention and treatment of osteoclast-associated Ig-like receptor (OSCAR)-induced diseases.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide the use of adefovir, a pharmaceutically acceptable salt or prodrug thereof for the manufacture of a treatment for osteoclast-associated Ig-like receptor (OSCAR)-induced diseases.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide an osteoclast-associated Ig-like receptor (OSCAR) inhibitor containing adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide a method for inhibiting osteoclast-associated Ig-like receptor (OSCAR) comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide a food composition for preventing or improving osteoclast-associated Ig-like receptor (OSCAR)-induced diseases, comprising adefovir or a food-acceptable salt thereof as an active ingredient.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide a quasi-drug composition for preventing or improving osteoclast-associated Ig-like receptor (OSCAR)-induced diseases, comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient. is to provide.
  • OSCAR osteoclast-associated Ig-like receptor
  • Another object of the present invention is to provide a feed additive composition for preventing or improving osteoclast-associated Ig-like receptor (OSCAR)-induced diseases, comprising adefovir or a feed-acceptable salt thereof as an active ingredient. It is done.
  • OSCAR osteoclast-associated Ig-like receptor
  • the present invention provides a pharmaceutical for the prevention or treatment of osteoclast-associated Ig-like receptor (OSCAR)-induced diseases comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof represented by the following formula (1) as an active ingredient.
  • a composition is provided.
  • the present invention provides adefovir, a pharmaceutically acceptable salt or prodrug thereof represented by Formula 1 for use in the treatment of oskar-induced diseases.
  • the present invention provides the use of adefovir, a pharmaceutically acceptable salt or prodrug thereof represented by Formula 1 for the manufacture of a therapeutic agent for oskar-induced diseases.
  • the compound name of adefovir of the present invention is 9-(2-(phosphonomethoxy)ethyl)adenine (PMEA) and ((2-(6-amino-9H-purin-9-yl)ethoxy)methylphosphonic acid. is also referred to.
  • an acid addition salt formed by a free acid is useful.
  • Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated and the mixture then evaporated to dryness, or the precipitated salt can be filtered off with suction.
  • an acid or alcohol e.g., glycol monomethyl ether
  • organic acids and inorganic acids can be used as free acids.
  • Hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid can be used as organic acids.
  • a pharmaceutically acceptable metal salt can be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is particularly pharmaceutically suitable to prepare sodium, potassium or calcium salts as metal salts, and the corresponding silver salts are obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the invention include salts of acidic or basic groups that may be present in the compounds of the invention.
  • pharmaceutically acceptable salts include sodium, calcium, and potassium salts of hydroxy groups
  • other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, and dihydrogen.
  • phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts and methods or processes for producing salts known in the art. It can be manufactured through.
  • Prodrug of the present invention refers to a substance that is transformed into the parent drug in vivo.
  • Prodrugs are often used because they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be.
  • a prodrug may also have improved solubility in a pharmaceutical composition than the parent drug.
  • a prodrug is administered as an ester (prodrug) to facilitate transport across cell membranes where water solubility is detrimental to fluidity, but once inside the cell where water solubility is favorable, it is metabolized into the active carboxyl group. It may be a compound that is hydrolyzed by acid.
  • Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolically converted to reveal the active site.
  • Adefovir of the present invention can be administered as a prodrug to increase the activity, bioavailability, and stability of nucleosides or to modify their properties.
  • alkylation, acylation or other lipophilic modification of the hydroxy, mono, di or triphosphate of the nucleoside will increase the stability of the nucleoside.
  • substituent groups that can replace one or more hydrogens on a hydroxyl or phosphate moiety include alkyls, aryls, steroids, carbohydrates including sugars, 1,2-diacylglycerol, and alcohols. Numerous examples are found in R. Jones and N.
  • Adefovir is useful as an antiviral treatment and can be formulated as adefovir depivoxil.
  • Adefovir dipivoxil is a prodrug of adefovir developed to improve the low oral absorption rate of adefovir.
  • Adefovir dipivoxil has the structural formula of formula 2 below, and its compound name is [2-[bis(pivaloyloxy)methoxyphos. It is pinylmethoxy]ethyl]adenine (bis-POM PMEA).
  • Adefovir dipivoxil is a nucleotide reverse transcriptase inhibitor that shows excellent therapeutic effects against hepatitis B and HIV, and is sold under the trade name Hepsera.
  • adefovir dipivoxil is an ester prodrug (prodrug) of adefovir, a nucleotide analog used in the treatment of chronic hepatitis B.
  • Adefovir dipivoxil is absorbed into liver cells and cleaved into adefovir by intracellular esterases. Adefovir is then phosphorylated first by adenylate kinase and then into adefovir diphosphate by nucleoside diphosphate kinase.
  • Adefovir diphosphate is an analog of deoxyadenosine triphosphate (dATP) and is known to bind to viral DNA polymerase and compete with dATP for binding to the growing DNA strand.
  • the prodrug of adefovir of the present invention may be adefovir depivoxil represented by Formula 2 above, but is not limited thereto.
  • the osteoclast-associated Ig-like receptor (OSCAR)-induced disease of the present invention may include, but is not limited to, cancer, hypertension, bone metabolic disease, chronic inflammatory lung disease, cardiovascular disease, atherosclerosis, or diabetes.
  • the bone metabolic disease of the present invention may be osteoporosis, arthritis, periodontal disease, fracture, or Paget's disease, and the arthritis may be osteoarthritis or rheumatoid arthritis, but is not limited thereto.
  • Bone metabolic disease of the present invention refers to a bone-related disease caused by an imbalance between osteoblasts and osteoclasts.
  • the bone metabolic diseases include bone destruction due to pathological bone diseases such as osteoporosis, arthritis, periodontal disease, fractures, or Paget disease caused by excessive bone resorption by osteoclasts. Diseases that promote, but are not limited to, are included.
  • the osteoporosis refers to a condition in which bone strength is weakened due to a decrease in bone quantity and qualitative changes, making fractures more likely to occur. Bone protects various organs in the human body, functions as a storage site for substances necessary for the body, such as calcium, and maintains homeostasis through the balance between osteoclasts that break down bone present in bone tissue and osteoblasts that produce bone. do. In the case of osteoporosis, the activity of two cells becomes unbalanced and excessive bone destruction by osteoclasts occurs, causing the disease to develop and progress.
  • the arthritis refers to a joint disease accompanied by inflammation in one or more joint areas.
  • the common form of arthritis is osteoarthritis, in which inflammation and pain occur due to damage to the bones and ligaments forming the joint due to gradual damage or degenerative changes in the cartilage that protects the joint.
  • Arthritis of the present invention is a disease accompanied by bone loss in the joint area, and the type is not particularly limited, but may be osteoarthritis or rheumatoid arthritis.
  • Osteoarthritis of the present invention also called degenerative arthritis, is a chronic disease in which damage to the bones, cartilage, and ligaments that form joints occurs due to damage or degenerative changes in cartilage, causing inflammation and pain. Osteoarthritis occurs in almost all joints in the body, including fingers, knees, hips, lower back, and neck. The main symptoms of osteoarthritis are repetitive pain, joint stiffness, decreased mobility, and loss of function. The clinical course usually progresses slowly, and as the disease progresses to a certain extent, the joint surface becomes irregular due to loss and degeneration of the articular cartilage, causing severe pain, and gradual movement disorders, which greatly interfere with daily life. Deformation also occurs.
  • Chondrocyte death is regulated downstream of the OSCAR receptor by the regulation of TRAIL and OPG. Collagen degradation due to shock and aging can activate OSCAR on the surface of chondrocyte cells in the extracellular matrix, thereby inducing cell death of chondrocyte cells.
  • OSCAR a cell membrane surface receptor of chondrocytes, plays an important role in controlling cartilage degeneration, this means that osteoarthritis can be caused by OSCAR.
  • Soluble OSCAR levels in rheumatoid arthritis are also related to the severity of the disease and the risk of cardiovascular disease.
  • OSCAR-collagen signaling in monocytes plays a pro-inflammatory role and may contribute to the pathogenesis of rheumatoid arthritis.
  • the periodontal disease refers to an inflammatory condition of the tooth-supporting tissue caused by bacteria, and can be divided into gingivitis and periodontitis.
  • the cause of the disease is oral bacteria forming a bacterial film on the teeth due to poor oral hygiene.
  • Dental biofilm refers to a mass of bacteria that grows after sticking to the tooth surface using the sticky substance in saliva as an adhesive. If the bacterial film on the teeth is left untreated, it can become inflamed, causing gums to bleed and bad breath. These symptoms are called gingivitis. As gingivitis progresses further, the gaps between the teeth and gums become deeper, forming periodontal pockets, and the bacteria that cause periodontal disease multiply here, causing periodontitis.
  • the fracture refers to a condition in which the continuity of a bone, epiphyseal plate, or joint surface is abnormally broken, and refers to a break in the bone.
  • causes of fractures include trauma such as traffic accidents, industrial accidents, bone changes due to diseases such as osteoporosis, bone cancer, and metabolic disorders, and repetitive stress on the bones due to sports or load.
  • fracture conditions can be classified into crack fractures, greenstick fractures, transverse fractures, filiform fractures, spiral fractures, segmental fractures, comminuted fractures, avulsion fractures, compression fractures, depressed fractures, etc.
  • Paget's disease refers to a localized bone disease in which bone remodeling is excessively promoted and a wide area of the skeletal system is invaded.
  • the pathological mechanism of Paget's disease is known to be a combination of an excessive increase in bone resorption by osteoclasts, which have the function of cleaning bones, and an increase in new bone formation by osteoblasts, which have the function of making bones as a compensation.
  • the newly formed bone in Paget's disease of bone is known to be structurally disordered and very vulnerable to bone deformation and fracture.
  • the pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof of the present invention as an active ingredient has oscar inhibitory activity and promotes differentiation of chondrocytes. Since it shows cartilage regeneration activity even after cartilage degeneration, it can have a preventive or therapeutic effect on the above diseases.
  • the cancer of the present invention may be bladder cancer, breast cancer, cholangiocarcinoma, colon adenocarcinoma, esophageal cancer, head and neck cancer, renal induced cell carcinoma, rectal adenocarcinoma, gastric adenocarcinoma, or thyroid carcinoma, but is not limited thereto.
  • OSCAR can promote malignancy in several cancer types, with enhanced metastasis associated with a suppressive immune microenvironment. The group with high OSCAR had a statistically significantly higher metastatic status. High expression of OSCAR is significantly associated with poor prognosis for many carcinomas, serving as a biomarker when considered together with a suppressive immune microenvironment.
  • the pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof of the present invention as an active ingredient has oscar inhibitory activity, and is therefore effective against the above-mentioned carcinomas. It can have preventive or therapeutic effects.
  • Hypertension of the present invention refers to an abnormally elevated state of blood pressure, and in specific clinical terms, systolic blood pressure (systolic blood pressure) measured at rest is 150 to 160 mmHg or more in adults, and diastolic blood pressure (diastolic blood pressure) is 90 to 95 mmHg or more. The case is treated as high blood pressure.
  • OSCAR is increased compared to the non-hypertensive control model. Therefore, in the prevention or treatment of hypertension as described above, the pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof of the present invention as an active ingredient has oscar inhibitory activity, and thus prevents the hypertension. Or it may have a therapeutic effect.
  • the chronic inflammatory lung disease of the present invention may be, but is not limited to, chronic obstructive pulmonary disease (COPD), emphysema, pneumonia, or tuberculosis.
  • COPD chronic obstructive pulmonary disease
  • OSCAR is a receptor for Surfactant Protein D that activates the release of TNF- ⁇ from human CCR2 + inflammatory monocytes.
  • the OSCAR:SP-D interaction may be a potential therapeutic target in chronic inflammatory diseases of the lung and several other diseases associated with tissue accumulation of SP-D, infiltration of inflammatory monocytes, and release of TNF- ⁇ .
  • Serum SP-D levels are associated with lung function or health status in patients with severe chronic obstructive pulmonary disease (COPD) and susceptibility to chronic and infectious lung diseases such as emphysema, pneumococcal lung disease, and tuberculosis.
  • COPD chronic obstructive pulmonary disease
  • the pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof of the present invention as an active ingredient has oscar inhibitory activity, It may have a preventive or therapeutic effect on inflammatory lung disease.
  • Atherosclerosis refers to dysfunction of arterial blood vessels due to lipid accumulation within the walls of arterial blood vessels forming lipid streaks or atherosclerotic plaques.
  • the resulting reduction in arterial vasomotor function due to plaque formation, luminal stenosis and even thrombosis affects the blood supply of tissues and organs supplied by the arteries, resulting in local or global ischemia of tissues and organs.
  • Diabetes is a metabolic disease caused by the abnormal action of insulin and is characterized by hyperglycemia, which increases the concentration of glucose in the blood. Hyperglycemia causes various symptoms and signs and excretes glucose in the urine.
  • Oscar is a novel receptor regulated by oxidized low-density lipoproteins in human endothelial cells.
  • oxidized low-density lipoprotein oxLDL
  • oxLDL oxidized low-density lipoprotein
  • oxLDL oxidized low-density lipoprotein
  • oxLDL oxidized low-density lipoprotein
  • In vivo modified LDL increases OSCAR expression.
  • In vivo modified LDL from diabetic patients increases OSCAR mRNA expression in human endothelial cells.
  • the pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof of the present invention as an active ingredient has Oscar-inhibiting activity, and thus, the diseases It can have a preventive or therapeutic effect.
  • the pharmaceutical composition of the present invention can reduce mRNA expression of cartilage degeneration markers.
  • the cartilage degeneration markers include matrix metalloproteinases (MMP)-3, MMP-13, and ADAMTS-5, which function to decompose the extracellular matrix (ECM) of cartilage cells.
  • MMP-3 functions to degrade collagen types II, III, IV, IX and X, proteoglycans, fibronectin, laminin and elastin. also. It also activates other MMPs such as MMP-1, MMP-7, and MMP-9. Therefore, MMP-3 is considered the most important factor in the reorganization of connective tissue.
  • MMP-9 degrades collagen types IV and V and other extracellular matrices, and MMP-12 functions to degrade elastin.
  • MMP-13 is a collagen-degrading enzyme known as collagenase 3 in humans, and is mainly expressed in the skeleton because it is necessary for the reconstruction of the collagen matrix during the fetal development stage. Very high expression has been observed in pathological situations, such as carcinoma, rheumatoid arthritis, and osteoarthritis.
  • the cartilage degeneration marker may be MMP3 or MMP13, but is not limited thereto.
  • the pharmaceutical composition of the present invention increases the mRNA expression of cartilage regeneration markers.
  • the cartilage regeneration marker may be COL2A1 or SOX9, but is not limited thereto.
  • the SOX9 (SRY (sex determining reiong Y)-box9) is the most important in forming cartilage matrix such as collagen type 2 and aggrecan, which constitute the matrix of cartilage in existing cartilage cells. It is a well-known master transcription factor.
  • the pharmaceutical composition can increase the survival rate of cartilage cells.
  • the inflammatory cytokine IL-1 ⁇ was treated to activate the inflammatory response and chondrocyte death signaling system, and after treating the chondrocytes with adefovir and further culturing, CCK- 8 As a result of confirming cell survival through analysis, it was confirmed that chondrocytes were significantly recovered and survived at adefovir concentrations of 5 to 10 ⁇ M.
  • the pharmaceutical composition can increase the differentiation of cartilage cells and increase the regeneration of cartilage tissue.
  • adefovir was injected into the knee cavity of an animal model in which osteoarthritis was induced by DMM surgery, the effect of recovering osteoarthritis that had already occurred and regenerating cartilage was confirmed.
  • the pharmaceutical composition may have a cartilage regeneration effect even after cartilage degeneration.
  • the effect of cartilage regeneration was confirmed even when intra-articular injection was administered from the second half of the 4th week of the total 8-week period, rather than immediately intra-articularly, in an animal model in which osteoarthritis was induced by DMM surgery. .
  • composition of the present invention may be administered by any method selected from the group consisting of local administration, topical administration, and injection, and the administration by injection may be intra-articular injection. It is not limited to this.
  • Prevention of the present invention refers to all actions that inhibit or delay the occurrence of Oscar-induced disease by administering the pharmaceutical composition of the present invention.
  • Treatment of the present invention refers to all actions that allow treatment of an Oscar-induced disease by administering the pharmaceutical composition of the present invention to a subject in need of treatment of an Oscar-induced disease.
  • the pharmaceutical composition of the present invention can be prepared in the form of a pharmaceutical composition for the treatment of OSCAR-induced diseases, further comprising appropriate carriers (natural or unnatural carriers), excipients or diluents commonly used in the preparation of pharmaceutical compositions.
  • the pharmaceutical composition can be formulated and used in the form of a sterile injectable solution that can be administered according to conventional methods.
  • carriers, excipients, and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, and calcium.
  • examples include silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, collagen, etc.
  • aqueous solutions such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • sterilized aqueous solutions non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, ointments (for example, dental implants, etc.) may be included.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.
  • a base for suppositories witepsol, macrogol, tween 61, cacao, laurin, glycerogeratin, etc. can be used.
  • Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc.
  • Such solid preparations may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the above active ingredients. Additionally, in addition to simple excipients, lubricants such as magnesium stearate and talc can also be used.
  • it can be prepared by adding various excipients, such as wetting agents, sweeteners, fragrances, and preservatives.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and preparations.
  • Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • Wethepsol, Macrosol, Tween 61, cacao, laurin, glycerogelatin, etc. can be used as a base for suppositories.
  • the content of adefovir contained in the pharmaceutical composition of the present invention is not particularly limited, but may be included in an amount of 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight, based on the total weight of the final composition.
  • the pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount.
  • the pharmaceutically effective amount of the present invention is an amount sufficient to treat or prevent a disease with a reasonable benefit/risk ratio applicable to medical treatment or prevention.
  • the effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, gender, the patient's sensitivity to the drug, the administration time, route of administration and excretion rate of the composition of the present invention used, treatment period, It can be determined according to factors including the composition of the present invention used and the drugs used in combination or concurrently with it, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention can be administered alone or in combination with a known pharmaceutical composition for treating oskar-induced diseases. It is important to consider all of the above factors and administer the amount that will achieve the maximum effect with the minimum amount without side effects.
  • the appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity, and is skilled in the art. can be appropriately selected.
  • the frequency of administration of the pharmaceutical composition of the present invention is not particularly limited, but may be administered once a day or divided into multiple doses.
  • Subjects for administration of the present invention include, but are not particularly limited to, humans, monkeys, cows, horses, pigs, sheep, chickens, cats, dogs, mice, rabbits, etc.
  • the present invention provides a method of treating Oscar-induced disease, comprising administering a pharmaceutical composition containing adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient to a subject suspected of having Oscar-induced disease. .
  • the treatment method of the present invention includes administering a pharmaceutically effective amount of the pharmaceutical composition into a subject suspected of having oskar-induced disease.
  • the subject refers to all mammals including dogs, cows, horses, rabbits, mice, rats, chickens or humans, but the mammals of the present invention are not limited to the above examples.
  • the pharmaceutical composition can be administered parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intraarticularly and intranasally, and for local treatment, if necessary, by any suitable method including intralesional administration.
  • the preferred dosage of the pharmaceutical composition of the present invention varies depending on the subject's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art.
  • adefovir, a pharmaceutically acceptable salt or prodrug thereof represented by Formula 1 can be used as a method for producing a therapeutic agent for oskar-induced diseases.
  • the present invention provides an oskar inhibitor comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient.
  • the Oscar inhibitor of the present invention can inhibit cartilage degeneration markers, promote cartilage regeneration markers, alleviate inflammation, promote differentiation and regeneration of cartilage cells, and alleviate cartilage degeneration.
  • the Oscar inhibitor can prevent or treat Oscar-induced diseases.
  • the Oscar-induced disease may include, but is not limited to, cancer, hypertension, bone metabolic disease, chronic inflammatory lung disease, cardiovascular disease, atherosclerosis, or diabetes.
  • the present invention provides a food composition for preventing or improving Oscar-induced disease, comprising adefovir or a foodologically acceptable salt thereof as an active ingredient.
  • adefovir of the present invention When using adefovir of the present invention as a food additive, it can be added as is or used with other foods or ingredients, and can be used appropriately according to conventional methods.
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use.
  • the food composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, and alcohol.
  • it may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.
  • the food can be manufactured in dosage forms such as tablets, granules, powders, capsules, liquid solutions, and pills according to known manufacturing methods.
  • adefovir of the present invention as an active ingredient, there are no particular restrictions on other ingredients, and various common flavoring agents or natural carbohydrates may be included as additional ingredients.
  • the present invention provides a quasi-drug composition for preventing or improving oskar-induced diseases, comprising adefovir, a pharmaceutically acceptable salt or prodrug thereof as an active ingredient.
  • Quasi-drugs of the present invention refer to products with a milder effect than pharmaceuticals among products used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases in humans or animals.
  • quasi-drugs are used for medicinal purposes. This excludes articles that can be used, and includes fibers or products used to treat or prevent diseases in humans or animals, products that have a minor effect on the human body or are not used directly, and are not instruments or machines, and similar products.
  • adefovir of the present invention When adding adefovir of the present invention to a quasi-drug composition for the purpose of preventing or improving oskar-induced diseases, adefovir can be added as is or used together with other quasi-drug ingredients, and can be used appropriately according to conventional methods.
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use.
  • the present invention provides a feed additive composition for preventing or improving Oskar-induced disease, comprising adefovir or a feedologically acceptable salt thereof as an active ingredient.
  • the feed additive of the present invention is a general term for substances added in trace amounts to animal feed for nutritional or specific purposes.
  • it refers to substances added for the purpose of preventing or improving Oscar-induced diseases.
  • animals are a concept that includes livestock and pets.
  • the feed additive of the present invention may further include binders, emulsifiers, preservatives, etc. added to prevent quality deterioration, and amino acids, vitamins, enzymes, probiotics, flavoring agents, and non-protein nitrogen added to increase utility. It may additionally include compounds, silicate agents, buffers, colorants, extractants, oligosaccharides, etc. In addition, it may additionally include feed mixtures, etc., but is not limited thereto.
  • the present invention relates to a composition for preventing or treating OSCAR-induced diseases containing adefovir as an active ingredient.
  • the composition is an OSCAR inhibitor that reduces OSCAR mRNA expression, relieves inflammation, and differentiates and regenerates chondrocytes. Through promotion, it can be useful in the treatment of OSCAR-induced diseases, including bone metabolic diseases.
  • Figure 1 is a diagram showing a schematic diagram of drug virtual search technology using artificial intelligence.
  • Figure 2 is a diagram showing a schematic diagram of a binding experiment between OSCAR and a compound.
  • Figure 3 is a diagram showing the results of quantifying the effect of Top 1 to 5, which are OSCAR inhibitory substances, by OSCAR mRNA expression.
  • Figure 4 is a diagram showing the effects of adefovir on controlling OSCAR signaling and inflammatory response signaling in primary chondrocytes.
  • Figure 5 is a diagram showing that adefovir promotes chondrocyte differentiation in bone marrow-derived mesenchymal stem cells.
  • Figure 6 is a diagram showing the inhibitory effect of adefovir on chondrocyte death in an apoptosis activation model.
  • Figure 7 is a diagram showing the effect of alleviating osteoarthritis after intra-articular injection of adefovir into the knee of a mouse suffering from osteoarthritis.
  • OSCAR osteoclast-associated Ig-like receptor
  • sBEAR Bioactive compounds Enrichment by Assay Repositioning
  • Adefovir Cat# SML0240, was purchased and used from Sigma-Aldrich, St Louis, MO, USA.
  • Medial meniscus resection surgery is a representative surgical technique that can simulate the symptoms of human osteoarthritis.
  • the medial meniscus is excised by incising the medial part of the knee of C57BL/6J (WT) male mice aged approximately 10 to 12 weeks. After that, DMM surgery to cause cartilage wear was performed again for 8 to 10 weeks.
  • the C57BL/6J male mice were purchased from Japan SLC, Inc. (Hamamatsu, Japan).
  • Adenovirus has low immunogenicity and is very efficient at introducing genes into cells and tissues, so it is widely used as a tool for gene introduction.
  • Adenovirus Ad-Control (1060) and Ad-OSCAR (ADV-267721) were purchased from Vector Biolabs (Malvern, PA, USA). Intra-articular injection of an adenovirus with a gene expected to cause or progress osteoarthritis is a commonly used method of inducing osteoarthritis in mice.
  • Adenovirus (1 x 109 PFU in a total volume of 10 ⁇ l) was injected into the knee joints of mice once a week for 3 weeks. Mice were sacrificed 4 or 9 weeks after the first injection of adenovirus.
  • the present inventors induced osteoarthritis by intraarticular injection of adeno-OSCAR.
  • mice Two cartilage degeneration-inducing animal models of Examples 3-1 and 3-2 were used. Mice were housed in isolation rooms, no more than five per cage, at 24 to 26°C and humidity ranging from 30 to 60% on a 12-hour light/dark cycle. For each experiment, age- and gender-matched mice were used and randomly assigned to each experimental group. All animal experiments were approved by the Ewha Mans University Animal Research Institute Animal Care Committee (IACUC Protocol No: IACUC 21-076) and followed the National Research Council guidelines.
  • mice were fixed in 10% formaldehyde for >24 h at 4°C and dehydrated in 0.5 Methylenediaminetetraacetic acid (EDTA) in PBS (pH 7.4) for 2 weeks. After being limed, it was embedded in paraffin. Next, the paraffin block was cut into 5 ⁇ m sections and incubated with hematoxylin and eosin, 0.1% Safranin-O (s8884, Sigma-Aldrich, St Louis, MO, USA) and 0.05% Fastgreen FCF (f7258, Sigma-Aldrich). Aldrich, St Louis, MO, USA).
  • EDTA Methylenediaminetetraacetic acid
  • Articular cartilage destruction was scored using the standard OA (osteoarthritis) grading OARSI scale (0-6), and sclerosis and articular cartilage destruction were identified using Safranin-O staining and OsteoMeasureXP (OsteoMetrics, Inc., Atlanta, GA, USA), Image-pro plus (v4.5, Media Cybernetics, Inc., Rockville, USA), Adobe photoshop (v9.0, San Jose, CA, USA) and Olympus DP72 charge-coupled device camera ( v2.1, Olympus Corporation, Tokyo, Japan).
  • Subchondral osteosclerosis was determined by measuring the thickness of the subchondral bone plate (SBP). Knee joint sections were incubated overnight at 4°C with primary anti-OSCAR antibody (Cat# SC34235, Santa Cruz Biotechnology, Inc., Dallas, TX, USA and Biorbyt, LLC, St Louis, USA, 1:200 dilution). .
  • SBP subchondral bone plate
  • DAB 3,3'-diaminobenzidine peroxidase
  • MMP3 (Cat# Ab53015, Abcam, Cambridge, MA, USA, 1:50 dilution), MMP13 (Cat# Ab51072, Abcam, 1:25 dilution), Aggrecan (Cat# Ab1031, Abcam 1:100 dilution), COL2A1 (Cat # MAB8887, Sigma-Aldrich, St Louis, MO, USA, 1:50 dilution), ADAMTS5 (Cat# GTX100332, Genetex, Irvine, CA, USA, 1:200 dilution), SOX9 (Cat# ab185230, Abcam 1:50) dilution), TGF ⁇ (Cat# 3711s, Cell Signaling Technology, 1:25), p-smad2 (Cat# ab188334, Abcam 1:50 dilution), and p-smad3 (Cat# ab52903, Abcam 1:25 dilution) Additional immunostaining was performed using .
  • Articular cartilage cell death was determined using the TUNEL assay and a kit from Millipore (Apoptosis Detection kit, Lot #2397039, Temecula, CA, USA). The specimen was visualized using a fluorescence microscope, and the number of apoptotic articular chondrocytes was counted compared to the total number of cells.
  • cDNA complementary DNA
  • Caspase-3 and caspase-8 activities were determined using a caspase colorimetric assay kit (Biovision Research Products, Milpitas, CA, USA). Articular chondrocyte lysates were incubated with substrates for caspase-3 (DEVD-pNA) or caspase-8 (IETD-pNA) for 2 hours at 37°C. The activity of each caspase was determined by measuring the absorbance at 405 nm.
  • OSCAR in order to identify the inhibitory effect and point of action of OSCAR within chondrocytes for the effective substance adefovir (EK1), which is a competitive inhibitor that inhibits the binding of OSCAR receptors to collagen, OSCAR was preliminarily overexpressed through adeno-adjacent virus in articular cartilage cells. An experiment was performed.
  • EK1 effective substance adefovir
  • chondrocytes were prepared by isolating cells from the femoral limb and tibial disc of ICR mice about 4 to 5 days old. Thereafter, cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin, and 100 ⁇ g/ml streptomycin, treated with hyaluronic acid, and inoculated with adeno-attached OSCAR virus. Through infection experiments, OSCAR was overexpressed in articular chondrocytes.
  • FBS fetal bovine serum
  • penicillin 100 units/ml
  • streptomycin 100 ⁇ g/ml streptomycin
  • adefovir is an effective substance for inhibiting OSCAR and has an excellent effect on inhibiting OSCAR.
  • the OSCAR signaling system was activated by culturing primary chondrocytes on a culture dish pre-coated with OSCAR-binding Collagen (OSC). Afterwards, adefovir, or EK1 substance, was treated to study the intracellular point of action as an OSCAR inhibitor in chondrocytes.
  • OSC OSC-binding Collagen
  • chondrocytes extracted from mouse joints were treated with 10 ng/ml of the inflammatory cytokine IL-1 ⁇ (interleukin-1 ⁇ ) to activate the inflammatory response signaling system, and then treated with adefovir.
  • cytokine IL-1 ⁇ interleukin-1 ⁇
  • Adefovir promotes cartilage regeneration markers (anabolic markers) in an inflammatory activity model.
  • cartilage regeneration markers When inflammation is activated, the expression of cartilage regeneration markers is suppressed, and adefovir was confirmed to significantly increase the expression of these markers. This suggests that the regulation of SOX9, a transcription factor that plays a key role in cartilage formation and development, is achieved through adefovir.
  • BMMSC bone marrow mesenchymal stem cells
  • the mesenchymal stem cells differentiate into chondrocytes among downstream chondrocytes, osteoblasts, and adipocytes ( Figure 5a).
  • Ad-OSCAR Ad-OSCAR
  • adefovir has an effect in controlling cartilage differentiation from stem cells and, in particular, has an effect in promoting differentiation into chondrocytes.
  • CCK8 assay was performed to determine whether adefovir affected the survival (cell viability) of chondrocytes.
  • OSCAR signaling system was activated by culturing primary chondrocytes on a plate pre-coated with OSCAR-binding collagen (OSC). Afterwards, the chondrocytes were cultured for 36 hours and then treated with the inflammatory cytokine IL-1 ⁇ to activate the inflammatory response and chondrocyte death signaling system.
  • OSC OSCAR-binding collagen
  • the effective concentration of adefovir that is, EK1
  • EK1 the effective concentration of adefovir
  • 5 ⁇ M and 10 ⁇ M the effective concentration of adefovir
  • cell survival was confirmed using the CCK8 assay.
  • chondrocytes were significantly recovered and survived at a concentration of 10 ⁇ M adefovir ( Figure 6).
  • OA osteoarthritis
  • OARSI grade which is an indicator for quantifying the degree of cartilage degeneration
  • degree of osteophyte formation which is one of the methods for determining OA
  • SBP subchondral bone plate
  • the adefovir, or EK1 substance, of the present invention was not administered intra-articular injection (IA injection) immediately after DMM surgery to induce osteoarthritis (OA) in mice, but was administered in the second half of the total 8-week experiment period. Intra-articular injections were administered starting from the 4th week.
  • composition containing adefovir of the present invention as an active ingredient regulates the OSCAR signaling system, and specifically, the composition reduces OSCAR mRNA expression, alleviates inflammation, and promotes differentiation and regeneration of chondrocytes to treat OSCAR bone metabolic diseases. It may be useful in treating induced diseases.

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Abstract

La présente invention concerne : une composition destinée à la prévention ou au traitement de maladies induites par OSCAR, comprenant de l'adéfovir en tant que principe actif ; et une méthode de traitement de maladies induites par OSCAR, comprenant une étape d'administration de la composition à un sujet atteint d'une maladie induite par OSCAR. La composition est un inhibiteur d'OSCAR qui réduit l'expression d'ARNm d'OSCAR, et a été identifiée comme ayant les effets d'atténuation de l'inflammation et de promotion de la différenciation et de la régénération de cellules cartilagineuses, et peut ainsi être efficacement utilisée dans le traitement de maladies induites par OSCAR comprenant des maladies osseuses métaboliques.
PCT/KR2023/015908 2022-10-19 2023-10-16 Composition destinée à la prévention ou au traitement de maladies induites par oscar, comprenant de l'adéfovir en tant que principe actif WO2024085557A1 (fr)

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