KR-102960952-B1 - Pharmaceutical compositions for preventing or treating bone diseases

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of bone diseases, and more specifically, by including a TCP-(MP)-Caffeic acid analog, it inhibits osteoclast differentiation and/or production and can exhibit excellent preventive or therapeutic effects for various bone diseases including osteoporosis.

Inventors

• 이태훈
• 조종현
• 이선우
• 김근중
• 김정선
• 김은애
• 최은랑
• 첸 지하오

Assignees

• 전남대학교산학협력단
• 동아대학교 산학협력단
• 조선대학교산학협력단

Dates

Publication Date

20260508

Application Date

20230809

Claims (4)

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (In the formula, R is hydrogen or t-butyldimethylsilyl).
2. A pharmaceutical composition for the prevention or treatment of any one bone disease 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, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] (In the formula, R is hydrogen or t-butyldimethylsilyl).
3. delete
4. A health functional food for improving any one of the bone diseases 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, comprising a compound represented by the following chemical formula 1 or a food-grade acceptable salt thereof: [Chemical Formula 1] (In the formula, R is hydrogen or t-butyldimethylsilyl).

Description

Pharmaceutical compositions for preventing or treating bone diseases The present invention relates to a pharmaceutical composition for the prevention or treatment of bone diseases. Bone tissue is a tissue where the processes of bone resorption by osteoclasts and bone formation by osteoblasts are continuously maintained. The differentiation of osteoblasts is promoted by signaling factors such as Bone Morphogenetic Protein 2 (BMP2). The differentiation of osteoclasts is promoted by the RANKL (Receptor Activator of Nuclear Factor Kappa-β Ligand) signaling molecule produced during the osteoblast differentiation stage, and apoptosis occurs once differentiation is complete. Therefore, it is important that the differentiation and activity of osteoblasts and osteoclasts occur in harmony during the normal bone regeneration process. When the equilibrium between osteoblasts and osteoclasts is disrupted and bone resorption outpaces bone formation, the calcium in the bone tissue decreases, causing the bone compaction to thin and the bone marrow cavity to widen. As the condition progresses, the bone weakens, making it susceptible to fractures even from minor impacts. The disease caused by these symptoms is osteoporosis. Osteoporosis refers to a condition in which the bone matrix becomes pathologically thin, leading to decreased bone density, weakened bone strength, and an increased risk of fracture. Skeletal strength is primarily formed and maintained by the bone matrix and the deposition of minerals within it, which is clinically reflected in bone density. Osteoporosis is classified into primary osteoporosis and secondary osteoporosis depending on its cause. Osteoclasts play a crucial role in inducing bone resorption in bone diseases such as osteoporosis, periostitis, and rheumatoid arthritis. Therefore, many efforts have been made to discover alternative drugs capable of treating bone diseases by inhibiting osteoclast differentiation. Figure 1 schematically illustrates the synthesis process of a TCP-(MP)-caffeic acid (Tranylcypromine-Methylpiperidine-Caffeic acid) analog. Figure 2 relates to the inhibitory effect (in vitro) of osteoclast formation of TCP-(MP)-caffeic acid analogs (CD-I-448 and 478) and three TCP-caffeic acid analogs (CD-I-389, CD-I-439, CD-I-442) corresponding to the compound of Formula 1 of the present invention. A and B show the results of fixing and staining mature osteoclasts using a TRAP (Tartrate-Resistant Acid Phosphatase) staining kit after treating bone marrow-derived macrophages (BMDM) with each novel LSD1 inhibitor (CD-I-389, CD-I-439, CD-I-442, CD-I-448, and CD-I-478) for 4 days in induction medium supplied with M-CSF (Macrophage-colony stimulating factor) (30 ng/mL) and RANKL (50 ng/mL) (A), and the results 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 shows the results of an in vitro LSD1 (Lysine-specific histone demethylase 1) activity assay. CTRL (DMSO treatment) is the control group. D and E show the effects of CD-I-448 and CD-I-478, corresponding to the compound of Formula 1, on protein methylation in BMDM (bone-marrow derived macrophage) using the LSD1 activity x-in vivo assay. MR (groups treated with M-CSF and RANKL) and GSK-LSD1 (group treated with GSK-LSD1 Dihydrochloride) are controls. F and G show the results of staining primary calvarial cells using an Alkaline Phosphatase (ALP Staining) assay kit after treating the cells with BMP2 (100 ng/mL) and incubating them with DMSO or a labeled novel LSD1 inhibitor (2 μM) for 9 days (F), and the ALP-positive density (%) expressing osteoblast differentiation measured by Image J (G). BMP2 is the control. Data reflect three independent experiments (scale bar: 100 μm. * p < 0.05 and ** p < 0.05 compared to control DMSO). Figure 3 relates to the dose-dependent inhibitory effect of TCP-(MP)-caffeic acid analogs on osteoclast formation (in vitro). A to D show the results of fixing and staining the formed mature osteoclasts using a TRAP staining kit after culturing BMDM for 4 days in an induction medium supplied with M-CSF (30 ng/mL) and RANKL (50 ng/mL) with or without the indicated dose of CD-I-448 (A), and the calculated area of TRAP-positive multinucleated osteoclasts (B), number of cells by nuclear type (C), and total number of cells per well (D). MR (group treated with M-CSF and RANKL) is the control group. E to G show the osteoclast bone resorption analysis effect (in vitro) evaluating the effect of CD-I-448 (E), the supernatant fluorescence analysis results of the indicated group (F), and the calculated resorbed pore area (%) of the indicated group using Image J software (G). MR (group treated with M-CSF and RANKL) is the control group. H indicates the cell viability assay results of CD-I-448 at the indicated doses. Data represent at least three independent experiments. (Scale bar: 200 μm. 0 μM - control group compar