Therapeutic agent for metabolic bone disease and pharmaceutical composition comprising the same
A PARG inhibitor-based treatment agent for metabolic bone diseases addresses the issue of serious side effects in existing treatments by enhancing osteoblast differentiation and suppressing osteoclast activity, providing an effective and safer therapeutic option.
Patent Information
- Application Number
- JP2023147362
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2023-09-12
- Publication Date
- 2025-03-25
AI Technical Summary
Current treatments for metabolic bone diseases such as osteoporosis often come with serious side effects like drug-related osteonecrosis of the jaw, atypical fractures, and hypocalcemia, with no established effective prevention methods.
A metabolic bone disease treatment agent containing a PARG inhibitor as an active ingredient, which enhances osteoblast differentiation and suppresses osteoclast differentiation, thereby reducing the number of osteoclasts and minimizing bone resorption.
The PARG inhibitor-based treatment agent effectively prevents and treats metabolic bone diseases with reduced risk of serious side effects, enhancing osteoblast activity while inhibiting osteoclast formation and activity.
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Abstract
Description
[Technical field]
[0001] The present invention relates to a therapeutic agent for metabolic bone diseases and a pharmaceutical composition containing the same, and more particularly to a therapeutic agent for metabolic bone diseases which is unlikely to cause serious side effects and a pharmaceutical composition containing the same. [Background technology]
[0002] For the treatment of metabolic bone diseases such as osteoporosis, therapeutic agents such as bisphosphonates and anti-RANKL antibodies are widely used. The above-mentioned bisphosphonate preparations have a strong affinity for hydroxyapatite in bone and are taken up into osteoclasts to induce cell death, thereby suppressing bone resorption. The above-mentioned anti-RANKL antibody drugs have strong affinity for RANKL and inhibit the binding of RANKL to the receptor RANK, which is expressed on the surface of osteoclasts and their precursor cells, thereby suppressing the formation of osteoclasts. Although these therapeutic drugs are known to be effective against metabolic bone diseases, serious side effects such as drug-related osteonecrosis of the jaw, atypical fractures, and hypocalcemia have been reported, and currently no effective treatment or prevention method has been established for osteoporosis (see Non-Patent Documents 1 and 2). [Prior art documents] [Non-patent literature]
[0003] [Non-Patent Document 1] "Today's Therapeutic Drugs 2020: Commentary and Handbook" by Akio Urabe et al., Nankodo, 2020 [Non-Patent Document 2] "Osteoporosis Prevention and Treatment Guidelines 2015 Edition" by the Osteoporosis Prevention and Treatment Guidelines Committee, Life Science Publishing, 2015 Summary of the Invention [Problem to be solved by the invention]
[0004] Under these circumstances, an object of the present invention is to provide a therapeutic agent for metabolic bone diseases which is unlikely to cause serious side effects, and a pharmaceutical composition containing the same. [Means for solving the problem]
[0005] However, in light of these circumstances, the present inventors conducted extensive research and discovered that the use of a PARG (poly(ADP-ribose) glycohydrolase) inhibitor, known for its anti-cancer use, as an active ingredient can promote osteoblast differentiation and inhibit the differentiation of osteoclast precursor cells into osteoclasts with bone resorption activity, and thus is useful for the prevention and treatment of metabolic bone diseases such as osteoporosis, thereby completing the present invention. In other words, the present invention is based on the discovery of unknown attributes of PARG inhibitors (enhancement of osteoblast differentiation and inhibition of osteoclast differentiation) and the finding that these attributes make PARG inhibitors suitable for a new application (treatment of metabolic bone diseases).
[0006] The present invention has the following aspects. [1] A therapeutic agent for metabolic bone diseases that contains a PARG inhibitor as an active ingredient. [2] The therapeutic agent for metabolic bone diseases described in [1], which is an osteoclast differentiation inhibitor. [3] The therapeutic agent for a metabolic bone disease according to [1] or [2], wherein the metabolic bone disease is at least one selected from the group consisting of osteoporosis, osteo-Behcet's disease, rheumatoid arthritis, osteogenesis imperfecta, periodontitis, and metastatic bone tumors. [4] The therapeutic agent for a metabolic bone disease according to any one of [1] to [3], wherein the PARG inhibitor is a compound having the formula (I) shown below, or a pharma- ceutically acceptable salt or solvate thereof. [ka] [5] The therapeutic agent for a metabolic bone disease according to any one of [1] to [4], wherein the PARG inhibitor is a compound represented by the following formula (II): [ka] [6] The therapeutic agent for metabolic bone diseases according to any one of [1] to [5], which is used in combination with at least one therapeutic agent for metabolic bone diseases selected from the group consisting of bisphosphonate preparations, anti-RANKL antibodies, and selective estrogen receptor modulators. [7] A pharmaceutical composition comprising the therapeutic agent for a metabolic bone disease according to any one of [1] to [6] together with a pharma- ceutically acceptable diluent and / or carrier. Effect of the Invention
[0007] Since the present invention contains a PARG inhibitor as an active ingredient, it is a therapeutic agent for metabolic bone diseases which is less likely to cause serious side effects than conventional therapeutic agents for metabolic bone diseases, and therefore can be suitably used as a pharmaceutical composition. [Brief description of the drawings]
[0008] [Figure 1] 1 shows micrographs of TRAP-positive multinucleated osteoclasts observed in an example and a comparative example. [Diagram 2] FIG. 2 is a graph showing the number of TRAP-positive multinuclear osteoclasts (after 3 days) in the Examples and Comparative Examples. [Diagram 3] FIG. 2 is a graph showing the number of TRAP-positive multinucleated osteoclasts (after 4 days) in the Examples and Comparative Examples. [Figure 4] FIG. 2 shows the results of analyzing gene expression of osteoclast differentiation markers (Trap, Dcstamp, Ctsk) in Example 1 and Comparative Example 1. [Diagram 5] FIG. 1 shows the results of analyzing gene expression of osteoclast differentiation markers (Trap, Dcstamp, Ctsk) in Example 5 and Comparative Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0009] The present invention will be described below based on examples of the mode for carrying out the present invention. However, the present invention is not limited to the embodiment described below.
[0010] In the present invention, when expressed as "X to Y" (X and Y are any numbers), unless otherwise specified, it includes the meaning of "X or more and Y or less", as well as "preferably larger than X" or "preferably smaller than Y". Furthermore, "x and / or y (x and y are optional configurations)" means at least one of x and y, and means the following three cases: x only, y only, and x and y.
[0011] The metabolic bone disease targeted by the present invention means a general disease in which the balance between bone formation and resorption is lost, resulting in a decrease in bone mass or a decrease in bone quality, such as osteoporosis, osteomalacia, hyperparathyroidism, hypoparathyroidism, vitamin D deficiency, etc., and also includes periodontitis, which has been reported to cause destruction of alveolar bone due to activation of osteoclasts. In particular, the present invention is useful for osteoporosis, osteo-Behçet's disease, rheumatoid arthritis, osteogenesis imperfecta, and periodontitis, which have been reported to be caused by abnormal activation of osteoclasts. Furthermore, the metabolic bone disease targeted by the present invention includes metastatic bone tumors. In the process of bone metastasis, osteoclasts are activated and bone resorption is promoted, and cancer cells metastasize to the bone-destroyed area, and it is considered appropriate to classify metastatic bone tumors as metabolic bone diseases. This is supported by the fact that, for example, bisphosphonates are used as therapeutic agents for bone metastasis of breast cancer, and anti-RANKL antibodies and bisphosphonates are used for bone lesions caused by bone metastasis of solid cancers.
[0012] In addition, in the present invention, treatment is meant to include not only targeting the cause of a disease to alleviate symptoms of the disease, slowing the progression of the disease, or curing the disease, but also the prevention of these diseases. And, containing as an active ingredient means containing as an ingredient having a therapeutic effect on metabolic bone diseases.
[0013] Furthermore, in the present invention, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. For example, "(1-6C)alkyl" means including (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. Also, the term "(m-nC)" or "(m-nC) group" means, when used alone or as a prefix, any group having m to n carbon atoms. And the term "halo" or "halogen" means fluoro, chloro, bromo, and iodo. And the term "heterocyclyl" includes both monovalent and divalent species.
[0014] <<Therapeutic agent for metabolic bone disease>> The therapeutic agent for metabolic bone disease according to one embodiment of the present invention contains a PARG inhibitor as an active ingredient. The PARG inhibitor and the therapeutic agent for metabolic bone disease according to the present invention contribute to the effects of the present invention by reducing the number of osteoclasts and suppressing the expression of osteoclast differentiation markers. Each component will be described in detail below.
[0015] <PARG inhibitor> First, poly(ADP-ribose) glycohydrolase (PARG) is an enzyme important for DNA damage repair and promotes DNA repair by removing poly ADP ribose from the DNA damage site. PARG inhibitors inhibit the function of such PARG, thereby inhibiting DNA repair and killing cancer cells. For example, they are known to be used as cancer therapeutic agents (anticancer agents). Specific examples of such PARG inhibitors include PDD00017273, JA2131, etc.
[0016] Among them, when the PARG inhibitor is a compound having the following formula (I), or a pharmaceutically acceptable salt or solvate thereof (hereinafter sometimes referred to as "compound etc. having formula (I)"), it is more certain that the number of osteoclasts can be reduced and the expression of osteoclast differentiation markers can be suppressed.
[0017] [ka]
[0018] In structural formula (I), R 1a is selected from the group consisting of fluoro, chloro, cyano, formyl, (1-2C) alkyl, (1-2C) haloalkyl, (2C) alkenyl or (2C) alkynyl, and is preferably methyl. And R 1b , R 1c , R 1d , R 1e are each independently selected from H, fluoro or methyl, with H being preferred.
[0019] In structural formula (I), X1 is CR2, and R2 is H or fluoro. Of these, it is preferable that X1 is CH. Also, X2 is CR3, and R3 is H or fluoro. Of these, it is preferable that X2 is CH. And, X3 is CR4, and R4 is selected from H, halo, cyano, (1-2C) alkyl, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, and (2C) alkynyl, or "-L4-L 4C -Q 4C Among them, X3 is preferably CH or CF.
[0020] "-L4-L 4C -Q 4C In the " group, L4 is absent or is a (1-3C) alkylene optionally substituted by (1-2C) alkyl or oxo. L 4C is absent or O, S, SO, SO2, N(R 4b ), C(O), C(O)O, OC(O), C(O)N(R 4b ), N(R 4b )C(O),N(R 4b )C(O)N(R4c ), S(O)2N(R 4b ) or N(R 4b )SO2. 4b and R 4c are each independently selected from hydrogen or (1-2C)alkyl. Q 4C is selected from the group consisting of hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl or heteroaryl. Also, Q 4C is halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, NR 4d R 4e , OR 4d , C(O)R 4d , C(O)OR 4d , O.C.(O)R 4d , C(O)N(R 4e )R 4d , N(R 4e )C(O)R 4d , S(O) y R 4d (wherein y is 0, 1 or 2), SO2N(R 4e )R 4d , N(R 4e )SO2R 4d or (CH2) z NR 4e R 4d where z is 1, 2 or 3. 4d and R 4e are each independently selected from H or (1-4C)alkyl.
[0021] Among the compounds having formula (I), the compound represented by the following formula (III) is particularly preferably used. An example of the PARG inhibitor having the compound represented by formula (III) is PDD00017273. PDD00017273 is described in detail in Japanese Patent No. 6673920.
[0022] That is, the compound represented by formula (III) is usually used as an active ingredient of a PARG inhibitor, but in the present invention, it is used as an active ingredient of a therapeutic agent for metabolic bone diseases.
[0023] [ka]
[0024] In addition, when the PARG inhibitor has a compound represented by the following formula (II), the number of osteoclasts can be further decreased and the expression of osteoclast differentiation markers can be suppressed. An example of such a PARG inhibitor is JA2131.
[0025] [ka]
[0026] Such a compound or a pharmacologically acceptable salt thereof used as a PARG inhibitor has an effect of promoting osteoblast differentiation and also has an effect of suppressing the differentiation of osteoclast precursor cells into osteoclasts having bone resorption activity. Therefore, the metabolic bone disease treatment agent of the present invention is useful for preventing or treating metabolic bone diseases and can be used as a drug, quasi-drug, cosmetic or food that is effective in treating metabolic bone diseases, or as a material to be incorporated into a drug, quasi-drug, cosmetic or food.
[0027] The metabolic bone disease treatment agent of the present invention contains a PARG inhibitor as an active ingredient, and can be formulated by appropriately mixing with pharma- ceutically acceptable carriers or additives according to known methods for producing pharmaceutical preparations, etc. (e.g., methods described in the Japanese Pharmacopoeia, etc.). That is, the therapeutic agent for metabolic bone diseases of the present invention may contain ingredients other than the PARG inhibitor, so long as they do not inhibit the effects of the present invention.
[0028] Examples of pharma- ceutically acceptable carriers include excipients, lubricants, binders, disintegrants, etc. in solid preparations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary. These can be used alone or in combination of two or more kinds.
[0029] The means of administration of the therapeutic agent for metabolic bone diseases of the present invention is not particularly limited, and examples thereof include oral administration, injection, and topical application to the skin, among which oral administration is preferred.
[0030] When the therapeutic agent for metabolic bone disease of the present invention is orally administered, the dosage form may be any of solid preparations such as tablets, granules, fine granules, powders, pills, capsules, dry syrup, etc., or liquid preparations such as semi-solid preparations, suspensions, syrup, etc., and when the therapeutic agent for metabolic bone disease of the present invention is used as a medicine, quasi-drug, or food, the dosage form of the medicine, quasi-drug, or food may be any of solid, semi-solid, liquid, etc.
[0031] When the therapeutic agent for metabolic bone diseases of the present invention is administered by injection, it can be used, for example, as an injectable preparation.
[0032] When the therapeutic agent for metabolic bone disease of the present invention is administered externally to the skin, it can be used, for example, as an external skin preparation, bath additive, etc. When used as an external skin preparation, examples of the dosage form include ointments, creams, milky lotions, gels, pastes, lotions, sprays, patches, etc. Furthermore, the external skin preparation can also be used, for example, as a skin lotion, beauty essence, pack, milky lotion, cream, sunscreen, sun oil, etc.
[0033] The therapeutic agent for metabolic bone diseases of the present invention is safe and has low toxicity, and can therefore be administered to, for example, humans, other mammals (eg, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.), and fish. Furthermore, the metabolic bone disease therapeutic agent of the present invention preferably contains the PARG inhibitor, which is the active ingredient of the present invention, in an amount of 0.01 to 100% (w / w) relative to the total amount of the therapeutic agent, although this varies depending on the dosage form, administration method, carrier, etc., and more preferably contains 0.1 to 95% (w / w), and even more preferably contains 1 to 50% (w / w) of the PARG inhibitor, which is the active ingredient of the present invention.
[0034] The dosage varies depending on the subject, symptoms, administration method, etc., but in the case of oral administration, for example, in a human weighing about 60 kg, the PARG inhibitor, which is the active ingredient of the present invention, is preferably administered at 0.1 to 1000 mg per day, more preferably 0.1 to 600 mg, and even more preferably 0.1 to 300 mg. The total dosage per day may be a single dose or a divided dose. In the case of divided administration, it is preferably 1 to 3 times a day, more preferably 1 to 2 times a day, and even more preferably once a day.
[0035] The therapeutic agent for metabolic bone disease of the present invention exhibits an effect of inhibiting osteoclast differentiation in addition to promoting osteoblast differentiation. It also has low cytotoxicity and few drug-related side effects compared to conventional therapeutic agents for metabolic bone disease, making it useful as a therapeutic agent that is both effective and safe.
[0036] Therefore, the therapeutic agent for metabolic bone disease of the present invention can be used in place of or in combination with other therapeutic agents for metabolic bone disease that have been used in the past. In particular, when used together with one or more therapeutic agents for metabolic bone disease selected from the group consisting of bisphosphonates, anti-RANKL antibodies, and selective estrogen receptor modulators, the therapeutic agent for metabolic bone disease of the present invention can improve the pathological condition more efficiently because the other therapeutic agents for metabolic bone disease and the therapeutic agent for metabolic bone disease of the present invention have different action sites. In addition, by using it together with other prior therapeutic agents for metabolic bone diseases, it is possible to exert a therapeutic effect at a low concentration, thereby reducing serious side effects such as osteonecrosis of the jaw and atypical fractures that have been reported with other prior therapeutic agents for metabolic bone diseases.
[0037] <<Pharmaceutical Composition>> The pharmaceutical composition of the present invention contains the therapeutic agent for metabolic bone diseases of the present invention together with a pharma- ceutically acceptable diluent and / or carrier. A wide variety of diluents and carriers can be used depending on the form of the pharmaceutical composition.
[0038] As the diluent, for example, a sterile aqueous solution, various organic solvents, etc. can be used. These can be used alone or in combination of two or more kinds.
[0039] As the carrier, for example, water, glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc. can be used in the case of oral liquid preparations (suspensions, solutions, elixirs, etc.), while for example, starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant, etc. can be used in the case of oral solid preparations. These can be used alone or in combination of two or more kinds.
[0040] The pharmaceutical composition of the present invention may contain ingredients other than the therapeutic agent for metabolic bone diseases of the present invention and the above-mentioned diluent and / or carrier, so long as the effects of the present invention are not impaired. EXAMPLES
[0041] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to the following examples as long as it does not depart from the gist of the present invention.
[0042] It is believed that the efficacy of the present invention can be demonstrated by demonstrating that the active ingredient, a PARG inhibitor, suppresses the differentiation of osteoclast precursor cells into osteoclasts having bone-resorbing activity. Based on this consideration, the following experiment was carried out.
[0043] <Examples 1 to 5, Comparative Example 1> It is known that RAW264 cells, which are osteoclast precursor cells, differentiate into osteoclasts with bone resorbing activity when cultured with the addition of RANKL. Therefore, RAW264 cells were cultured with a PARG inhibitor together with RANKL, and the degree of differentiation into osteoclasts was observed. That is, 7.9x10 RAW264 cells 3 cells / cm 2 The RAW264 cells were placed in a culture plate so that the cells were differentiated by adding 200 ng / mL RANKL and the types and amounts of PARG inhibitors or dimethyl sulfoxide (DMSO) shown in Table 1 below. The PARG inhibitors used in the examples are as follows: PARG inhibitor A: PDD00017273 (MedChemExpress) PARG inhibitor B: JA2131 (MedChemExpress)
[0044] [Table 1]
[0045] Then, 3 and 4 days after the start of differentiation induction, the cells were stained with TRAP to observe TRAP-positive multinucleated osteoclasts, and the degree of differentiation into osteoclasts was examined and the number of cells was calculated. The observation results are shown in Figure 1, and the calculated number of TRAP-positive multinucleated osteoclasts is shown in graphs in Figure 2 (after 3 days, Day 3) and Figure 3 (after 4 days, Day 4).
[0046] As shown in Figures 1 to 3, in the control (Comparative Example 1), the number of TRAP-positive multinuclear osteoclasts increased from Day 3 to Day 4 (the proportion of the colored area in the figure increased), whereas in Examples 1 to 5, the number of TRAP-positive multinuclear osteoclasts was significantly reduced compared to the control on Days 3 and 4. Thus, it was found that all of Examples 1 to 5 suppressed osteoclast differentiation. In particular, it was found that Examples 1 and 2 suppressed osteoclast differentiation at lower concentrations. The above-mentioned TRAP-positive multinucleated osteoclasts refer to "multinucleated osteoclasts that are TRAP-positive and contain three or more nuclei."
[0047] Furthermore, in Examples 1 to 5, the number of cells before and after differentiation induction was measured using a CCK assay, and no change in the number of cells was observed before and after differentiation induction, indicating that the use of Examples 1 to 5 does not cause cell death and is unlikely to cause serious side effects.
[0048] Furthermore, gene expression of osteoclast differentiation markers Trap, Dcstamp, and Ctsk was analyzed by qRT-PCR for Example 1 and Comparative Example 1. The results are also shown in FIG.
[0049] Then, gene expression of osteoclast differentiation markers Trap, Dcstamp, and Ctsk was analyzed by qRT-PCR for Example 5 and Comparative Example 1. The results are also shown in FIG.
[0050] From these results, it was suggested that in Example 1 and Example 5, the mRNA level of Trap was significantly decreased 4 days after differentiation induction, and the expression of Dcstamp and Ctsk also tended to be suppressed, suppressing osteoclast differentiation. In particular, it was found that Example 1 significantly reduced the expression level of osteoclast differentiation marker genes at a lower concentration than Example 5. [Industrial Applicability]
[0051] The therapeutic agent for metabolic bone diseases of the present invention is highly promising as a therapeutic agent for metabolic bone diseases and a pharmaceutical composition containing the same which are unlikely to cause serious side effects.
Claims
1. A therapeutic agent for metabolic bone diseases, comprising a PARG inhibitor as an active ingredient.
2. The therapeutic agent for metabolic bone diseases according to claim 1, which is an inhibitor of osteoclast differentiation.
3. 3. The therapeutic agent for metabolic bone diseases according to claim 1, wherein the metabolic bone disease is at least one selected from the group consisting of osteoporosis, osteo-Behcet's disease, rheumatoid arthritis, osteogenesis imperfecta, periodontitis and metastatic bone tumors.
4. 3. The therapeutic agent for metabolic bone diseases according to claim 1 or 2, wherein the PARG inhibitor is a compound having the following formula (I), or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 1】
5. The therapeutic agent for metabolic bone diseases according to claim 1 or 2, wherein the PARG inhibitor is a compound represented by the following formula (II): 【Chemistry 2】
6. 3. The therapeutic agent for metabolic bone diseases according to claim 1 or 2, which is used in combination with at least one therapeutic agent for metabolic bone diseases selected from the group consisting of bisphosphonate preparations, anti-RANKL antibody drugs, and selective estrogen receptor modulators.
7. 3. A pharmaceutical composition comprising the therapeutic agent for metabolic bone diseases according to claim 1 or 2 together with a pharma- ceutically acceptable diluent and / or carrier.