CN109106698A - Kirenol inhibits the application in osteoclast formation and/or osteoclast activity drug in preparation - Google Patents
Kirenol inhibits the application in osteoclast formation and/or osteoclast activity drug in preparation Download PDFInfo
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- CN109106698A CN109106698A CN201811074899.6A CN201811074899A CN109106698A CN 109106698 A CN109106698 A CN 109106698A CN 201811074899 A CN201811074899 A CN 201811074899A CN 109106698 A CN109106698 A CN 109106698A
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- osteoclast
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- kirenol
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- 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
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- 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
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- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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]
Abstract
The invention discloses the application of kirenol, its pharmaceutically acceptable derivates or its prodrug in the drug that preparation inhibits osteoclast formation and/or osteoclast activity.And be experimentally confirmed kirenol and can significantly inhibit external RANKL and osteoclastic precursor BMMs cell is induced to form osteoclast, directly inhibit being differentiated to form for osteoclast, inhibits osteoclastic bone resorption function.Kirenol has the characteristics that direct and significant ground inhibiting effect to the generation of osteoclast, osteoclastic activity, allow to be applied to the drug that preparation inhibits osteoclast formation and/or osteoclast activity, is also used as the drug that active constituent is used to prepare disease caused by treatment osteoclast overactivity.
Description
Technical field
The present invention relates to drug field, in particular to kirenol inhibits osteoclast formation and/or osteoclast in preparation
Application in active medicine.
Background technique
The bone resorption and osteoblast that the stabilization of bone metabolism needs osteoclast (Osteoclasts, OCs) to mediate
Dynamic equilibrium and coupling between the bon e formation effect that (Osteoblasts, OBs) is mediated, in healthy individuals, the two maintains function
Balance, and balance the generation that may cause skeletal diseases if breaking.
Osteoclast is the cell of unique responsible bone resorption in vivo.It can break up shape after activation by osteoclastic precursor
At the osteoclast for having functional maturation.Since the osteoclast of differentiation and maturation can absorb sclerotin, excessive activation be will cause
Bone loss, osteoporosis cause fracture pain, secondary reaction bone regeneration, or even deformity.Osteoclast overactivity is related
Disease it is many, classical has postmenopausal osteoporosis, and furthermore important there are also metastases osteoclasias, inflammation related bone
Destroy (rheumatoid arthritis, septic arthritis, periodontitis etc.) etc..Separately there are a variety of disease sclerotin such as diabetes, colitis
It is loose also to dramatically increase.Osteoclast cell activation correlation osteoclasia number of patients is huge, and only primary osteoporosis is (main comprising exhausted
Osteoporosis etc. after) just there are more than one hundred million patients in the whole world.
Osteoclast overactivity correlation osteoclasia kinds of Diseases multiplicity, the cause of disease is also greatly or even a disease
Some of it will belong to that etiology unknown is true or the refractory disease of the diversification cause of disease there are many correlative factor of falling ill.But
It is directly against osteoclast, the drug for inhibiting osteoclast to be differentiated to form may span across the disease cause of disease, directly improve relevant disease
Sick osteoclasia symptom, and effectively mitigate the relevant pains such as patient's fracture, pain.Therefore, osteoclast differentiation inhibitor is more closely
Become a kind of drug year, can be used for a variety of osteoclast overactivity correlation osteoclasia diseases such as postmenopausal osteoporosis.
Although treating the final energy of a variety of drugs of above-mentioned disease by improving the different approaches such as hormonal readiness, anti-inflammatory at present
Enough improve disease, but now clinic can directly against osteoclast osteoclast inhibitors it is seldom.In addition, although some
Drug can be directed to the cause of disease for example anti-inflammatory treatment osteoclasia disease such as rheumatoid arthritis, theoretically have directly or indirectly suppression
Osteoclast processed generates a possibility that with inflammatory osteoclasia, but in fact many common drugs can be induced brokenly by report instead
Osteocyte forms or aggravates osteoporosis.For example two for the treatment of rheumatoid arthritis, which commonly use, represents drug: glucocorticoid
(such as dexamethasone), methotrexate (MTX) can inhibit periphery or the lesion arthritis factor includes the generation of TNF α, but two medicines
It can cause osteoclasia.Glucocorticoid (such as dexamethasone) can promote that osteoclast is induced to generate in vitro, in vivo in animal and
Patient is easy to draw osteoporosis；Methotrexate (MTX) can also promote osteoclast formation after, cause osteoclasia.
And currently used osteoclast inhibitors are the inhibitor of bis phosphoric acid salt (such as zoledronic acid) and RANKL
Denosumab (promise monoclonal antibody).Drug quilt of both osteoclast inhibitors initially both as treatment postmenopausal osteoporosis
Approval listing, all goes through to increase new clinical indication-metastases osteoclasia in recent years.However, bis phosphoric acid salt is most
It needs drug administration by injection, be easy to cause the serious adverse reactions such as jawbone necrosis；And it is directed to the biology of osteoclast activation factor RANKL
Antibody preparation ground promise monoclonal antibody, needs subcutaneous administrations, price is more expensive.Therefore, clinical to need more conveniently take, is economical
Effective osteoclast inhibitors class drug.
Targeted inhibition osteoclast (OCs) differentiation is considered as reversing the most effective therapeutic strategy of osteoclasia, at present
A research hotspot as the field.Osteoclast originates from bone marrow mononuclear-macrophage lineage cell, in vivo must be according to
The some inducement induction differentiation and developments of Lai Yu are the mature osteoclast of multicore, are finally activated.It is now recognized that most direct activation is broken
The endogenous molecule of osteocyte is the ligand of the activation nuclear factor NF- κ B receptor of osteoblast or marrow stromal cell secretion
(receptor activation of nuclear factor NF-κB ligand,RANKL).RANKL passes through and osteoclastic thin
Nuclear factor NF- κ B receptor (receptor activation of nuclear factor NF- κ B, RANK) knot is activated on after birth
It closes, recruitment forms (the tumor neerosis factor receptor-associated of tumor necrosis factor associated receptor 6
Factor 6, TRAF6) and c-Src tyrosine kinase (c-Src tyrosine kinase, c-Src) complex, activate downstream
Signal path (NF- κ B, MAPK and Ca2+ access) activates nuclear factor Nuclear factor kappa B by intracellular signaling pathways
(nuelear factor kappa B, NF- κ B), Activating protein-1 (activator protein l, AP-1) and activating T cell
Nuclear factor c1 (nuclear factor of activated T cells cl, NFATc1) activates osteoclast related gene
Expression, such as anti-tartaric acid alkaline phosphatase (tartrate resistant acid phosphatase, TRAP), Metal Substrate
Matter proteinase 9 (tartrate resistant acid phosphatase, MMP-9), Integrin β_3 (integrin β 3) and group
It knits Proteinase K (cathepsin K), promotes osteoclast differentiation, enhance bone resorption activity, inhibit its apoptosis, eventually lead to brokenly
Osteocyte quantity increases, hyperfunction.
Kirenol is that the differentiation of a kind of pair of skeletonization has diterpene product (Kim M B, the Song Y, Hwang of facilitation
J K.Kirenol stimulates osteoblast differentiation through activation of the
BMP and Wnt/β-catenin signaling pathways in MC3T3-E1cells[J].Fitoterapia,
2014,98:59-65.), but the differentiation of osteoclast is generated kirenol and the influence of osteoclastic activity, and there is presently no phases
Report is closed, structural formula is as follows:
Summary of the invention
The purpose of the present invention is to provide kirenols to inhibit osteoclast formation and/or osteoclast activity drug in preparation
In application.
The technical solution used in the present invention is:
Kirenol, its pharmaceutically acceptable derivates or its prodrug inhibit osteoclast formation and/or osteoclastic in preparation
Application in the drug of cell activity.
Kirenol, its pharmaceutically acceptable derivates or its prodrug are treated caused by osteoclast overactivity in preparation
Application in the drug of disease.
Further, disease be primary osteoporosis, it is metastases osteoclasia, any one in inflammation correlation osteoclasia
Kind is a variety of.
Further, primary osteoporosis is postmenopausal osteoporosis.
Further, the relevant osteoclasia of inflammation be rheumatoid arthritis, it is septic arthritis, any in periodontitis
It is one or more.
A kind of drug inhibiting osteoclast formation and/or osteoclast activity can containing active constituent and pharmaceutically connect
The adjuvant received, active constituent are kirenol, its pharmaceutically acceptable derivates or its prodrug.
Further, inhibit osteoclast formation and/or the drug of osteoclast activity is peroral dosage form or exterior-applied formulation.
A kind of drug for treating disease caused by osteoclast overactivity contains active constituent and pharmaceutically acceptable
Adjuvant, active constituent are kirenol, its pharmaceutically acceptable derivates or its prodrug.
Further, inhibit osteoclast formation and/or the drug of osteoclast activity is peroral dosage form or exterior-applied formulation.
The beneficial effects of the present invention are: the invention discloses kirenol can inhibit in vitro osteoclast generation, activation and
Osteoclastic activity.And it is experimentally confirmed kirenol and can significantly inhibit external RANKL and induced osteoclastic precursor BMMs cell
Osteoclast is formed, being differentiated to form for osteoclast is directly inhibited, inhibits osteoclastic bone resorption function.Kirenol is to osteoclastic thin
The generation of born of the same parents, osteoclastic activity have the characteristics that direct and significant ground inhibiting effect, allow to be applied to preparation and inhibit osteoclast
Formed and/or osteoclast activity drug, be also used as active constituent be used to prepare treatment osteoclast overactivity lead
The drug of the disease of cause.
Detailed description of the invention
Fig. 1 is cells survival Experiment on Function result of the kirenol to Bone Marrow Macrophage (BMMs)；
Fig. 2,3 are for kirenol to osteoclastic precursor BMMs cell differentiation at the experimental result of the influence of osteoclast, in which:
RANKL be activate nuclear factor NF- κ B receptor ligand (note: compared with blank control group, ###P < 0.001；With RANKL group ratio
Compared with P < 0.001 * * *)；
Fig. 4,5 be influence of the kirenol to osteoclast osteoclastic activity experimental result, in which: RANKL be activation core because
Sub- NF- κ B receptor ligand (note: compared with blank control group,###P<0.001；Compared with RANKL group,***P<0.001)。
Specific embodiment
Below in conjunction with embodiment, the present invention is further explained, it should be appreciated that following embodiment be merely to illustrate the present invention and
It is not used in and limits the scope of the invention.
Embodiment 1
Kirenol acts on the cells survival of Bone Marrow Macrophage (BMMs)
BMMs cell 2 × 104The kirenol of various concentration is added in 96 orifice plates in a/hole plantation after staying overnight.Every group 3
Multiple holes.It is incubated for respectively for 24 hours, after 5d, remove supernatant, the 100 μ L of MTT of 0.5mg/ml is added in every hole, sets in 37 DEG C of incubators and is incubated for 4h
Afterwards, liquid is discarded supernatant, 150 μ L of DMSO is added, oscillation is measured in 570nm after ten minutes, with Genios Pro type Tecan microplate reader
Absorbance.As a result as shown in Figure 1, as seen from Figure 1, kirenol concentration≤62.5 μM all have no significant effect BMMs cells survival.
Embodiment 2
Kirenol is divided into the influence of osteoclast to Bone Marrow Macrophage (BMMs)
6-8 weeks C57BL/6 mouse femur and shin bone are taken, cuts off both ends after removing muscle, draws ice pre-cooling with syringe
A-MEM repeated flushing femur, shin bone ossis, go out marrow, until ossis whitens, 37 DEG C, 5%CO2Incubator is placed
Supernatant suspension is taken after 30 minutes.Cell presses 1 × 105/ ml density is inoculated in 96 orifice plates, in addition to negative control group, RANKL group and medicine
Object group is added M-CSF and RANKL, and final concentration is 100ng/ml, medicine group be added simultaneously 1.25 μM of concentration, 2.5 μM, 5 μM,
10 μM of kirenol, every group of 3 multiple holes.It changes within every 2 days liquid 1 time.In induction 4d row TRAP dyeing, observation is clapped under the microscope
According to as a result as shown in Fig. 2, and by the TRAP positive and being that osteoclast is counted (aubergine, Duo Gexi greater than 3 cores
It is osteoclast that born of the same parents, which are fused together), as a result as shown in Figure 3.
1 cells survival experimental result in conjunction with the embodiments selects the kirenol of 1.25 μM, 2.5 μM, 5 μM, 10 μM concentration dry
In advance, discovery kirenol can significantly inhibit external RANKL induction BMMs cell and form osteoclast.Prompt kirenol is able to suppress
The generation of osteoclast.
Embodiment 3
Experimental program inoculation BMMs cell is generated in being coated with artificial osteocomma with osteoclast in above-described embodiment 296 orifice plate culture of Osteo Assay washes away cell on the 7th day in induction, in 40 × Nikon inverted light microscope
Om observation is taken pictures, and is added as shown in figure 4, calculate bone resorption area percentage in every hole by Image-Pro Plus software,
As a result as shown in Figure 5.
The results show: 1.25 μM of concentration, 2.5 μM, 5 μM, 10 μM of kirenol can significantly reduce osteoclast in bone
The bone notch area that on piece is formed, has inhibiting effect for the bone resorption activity of osteoclast.
In summary osteoclastic precursor BMMs cell is induced to be formed as a result, kirenol can significantly inhibit external RANKL
Osteoclast directly inhibits being differentiated to form for osteoclast, inhibits osteoclastic bone resorption function.Kirenol can inhibit osteoclastic thin
Generation, activation and the osteoclastic activity of born of the same parents.
Claims (9)
1. kirenol, its pharmaceutically acceptable derivates or its prodrug inhibit osteoclast formation and/or osteoclastic thin in preparation
Application in the drug of cytoactive.
2. kirenol, its pharmaceutically acceptable derivates or its prodrug treat disease caused by osteoclast overactivity in preparation
Application in the drug of disease.
3. application according to claim 2, it is characterised in that: disease be primary osteoporosis, metastases osteoclasia,
Any one or more in inflammation correlation osteoclasia.
4. application according to claim 3, it is characterised in that: primary osteoporosis is postmenopausal osteoporosis.
5. application according to claim 3, it is characterised in that: the relevant osteoclasia of inflammation is rheumatoid arthritis, purulence
Any one or more in toxicity arthritis, periodontitis.
6. a kind of drug for inhibiting osteoclast formation and/or osteoclast activity, contain active constituent and pharmaceutically acceptable
Adjuvant, it is characterised in that: active constituent be kirenol, its pharmaceutically acceptable derivates or its prodrug.
7. drug according to claim 6, it is characterised in that: the inhibition osteoclast formation and/or osteoclast are living
Property drug be peroral dosage form or exterior-applied formulation.
8. a kind of drug for treating disease caused by osteoclast overactivity, contain active constituent and pharmaceutically acceptable auxiliary
Agent, it is characterised in that: active constituent is kirenol, its pharmaceutically acceptable derivates or its prodrug.
9. drug according to claim 8, it is characterised in that: the inhibition osteoclast formation and/or osteoclast are living
Property drug be peroral dosage form or exterior-applied formulation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811074899.6A CN109106698A (en) | 2018-09-14 | 2018-09-14 | Kirenol inhibits the application in osteoclast formation and/or osteoclast activity drug in preparation |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811074899.6A CN109106698A (en) | 2018-09-14 | 2018-09-14 | Kirenol inhibits the application in osteoclast formation and/or osteoclast activity drug in preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114366734A (en) * | 2020-10-14 | 2022-04-19 | 香港科技大学 | New application of psoralen and pharmaceutical composition thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150010923A (en) * | 2013-07-18 | 2015-01-29 | 연세대학교 산학협력단 | Composition for prevention, improvement or treatment of osteoporosis comprising kirenol or extract of Sigesbeckia spp. |
-
2018
- 2018-09-14 CN CN201811074899.6A patent/CN109106698A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150010923A (en) * | 2013-07-18 | 2015-01-29 | 연세대학교 산학협력단 | Composition for prevention, improvement or treatment of osteoporosis comprising kirenol or extract of Sigesbeckia spp. |
Non-Patent Citations (1)
| Title |
|---|
| LU YUE等.: "Effects of kirenol on bovine type II collagen-induced rat lymphocytes in vivo and in vitro.", 《J SOUTH MED UNIV》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114366734A (en) * | 2020-10-14 | 2022-04-19 | 香港科技大学 | New application of psoralen and pharmaceutical composition thereof |
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Application publication date: 20190101 |