CN104906081A - Application of compound in preparation of osteoarthritis therapeutic drug - Google Patents
Application of compound in preparation of osteoarthritis therapeutic drug Download PDFInfo
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- CN104906081A CN104906081A CN201510270396.6A CN201510270396A CN104906081A CN 104906081 A CN104906081 A CN 104906081A CN 201510270396 A CN201510270396 A CN 201510270396A CN 104906081 A CN104906081 A CN 104906081A
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Abstract
The invention discloses a kind of application of structure formula (I) compound in preparation treatment osteoarthritis drugs. It is verified by experiments, the expression for the MMP13 that structure of the invention formula (I) compound can obviously inhibit IL-1 β and TNFa to induce, while improving the expression of II Collagen Type VI and glycosaminoglycan, provide a kind of new approach and means for treatment osteoarthritis. This drug is clear with therapy target, and composition is single, easy to control on dosage, can be used for the treatment of osteoarthritis and improve the life quality of Human Osteoarthritis.
Description
Technical field
The present invention relates to field of medicaments, particularly relate to a kind of new medical use of compound, be specifically related to the application of compound PD0325901 in preparation treatment osteoarthritis drugs.
Background technology
Arthritis (osteoarthritis, OA) is about 13% at the total incidence of China, is wherein the most common with osteoarthritis, and sickness rate increases with the age and rises.According to latest data statistics, in the crowd more than 60 years old, x-ray has the osteoarthritis women sickness rate about 42.8% of performance, male about 21.5%, and women's sickness rate of Symptomatic osteoarthritis is about 15%, and male is about 5.6%.The one of the main reasons that osteoarthritis has become middle-aged and elderly people function invalidity, quality of life declines.Due to the development of society and the raising of medical level, the increase of population life, China will become the big country of osteoarthritis morbidity, the arthralgia that osteoarthritis shows and the stiff quality of life having a strong impact on person in middle and old age, also will bring heavy social burden simultaneously, therefore arthritic treatment be seemed particularly urgent and necessary.
The drug main of current clinical treatment osteoarthritis will adopt non-steroidal anti-inflammatory drugs (NSAIDs) and Chondroprotective agents and Chinese patent medicine preparation.NSAIDs is one of maximum medicine of global recipe quantity always, and this type of medicine exists obvious gastrointestinal reaction, limits it further and uses, though this kind of problem avoided by COX2 selective depressant, still have certain risk to cardiovascular system; Chondroprotective agents is as tieed up solid power, and daily expenses for medicine is used in 30 yuan/day, onset time long (﹥ 3 weeks), because of its expense and time cost high, have certain restriction to its popularization.And up to the present, above medicine is the chondrocyte that relevant report can reverse regression.
The world of medicine is being devoted to the medicine developing comparatively ideal treatment osteoarthritis always, finds safe and effective, that dosing is less, price is appropriate new Chinese medicine.
Compound PD0325901 is mainly used in the research in various cancer at present, and its active anticancer is confirmed in various human transplant's tumor, in the Human Tumor Models of research, has the tumor of more than 85% obviously to be suppressed by PD 0325901.
The structural formula (I) of compound PD0325901 is as follows:
Summary of the invention
The technical problem to be solved in the present invention is to provide the novelty teabag of structural formula (I) compound, the new opplication namely in preparation treatment osteoarthritis drugs.
Osteoarthritis occurs, mainly chondrocyte generation regression, and the regression main manifestations of chondrocyte is, promote the up-regulated of the matrix metalloproteinase MMP13 (Matrix metallopeptidase 13) of II Collagen Type VI and glycosaminoglycan degraded, and chondrocyte specific gene is lost as II Collagen Type VI and glycosaminoglycan etc. are expressed, if medicine can stop the expression of these genes to change, the medicine of osteoarthritis may be become.
At present in an experiment, find the expression of the MMP13 that PD0325901 (purchased from santacruz company) compound (i.e. structural formula (I) compound) can obviously suppress IL-1 β and TNFa to induce, improve the expression of II Collagen Type VI and glycosaminoglycan simultaneously.The present invention by the scorching factor of common inducing osteoarthritis as IL-1 β and the regression of TNFa Induction of chondrocytes, set up the cell model of osteoarthritis, add medicine (structural formula (I) compound) simultaneously, observe the effect of medicine, thus determine that structural formula (I) compound becomes the potential medicine of osteoarthritis, and be applied in the future the test of animal and human's body and establish experimental basis.
The invention provides the application of structural formula (I) compound in preparation treatment osteoarthritis drugs
Further, described structural formula (I) compound has the expression of the MMP13 suppressing IL-1 β and TNFa induction, improves the function of II Collagen Type VI and glycosaminoglycan expression simultaneously.
Further, described treatment osteoarthritis drugs contains structural formula (I) compound of pharmaceutical effective amount and pharmaceutically acceptable carrier.
Further, described medicine is made into the pharmaceutically acceptable dosage form of any one, such as tablet, capsule, granule, oral liquid, injection etc.
Utilize structural formula of the present invention (I) compound (in the present invention referred to as PD0325901), by various conventional screening assays, can filter out, with PD0325901, interactional material occur, as receptor, inhibitor or antagonist etc.PD0325901 is the inhibitor of signal path MAPK-MEK, mainly for the inhibitor of MEK molecule.
The administering mode of PD0325901 of the present invention is generally oral, but it has high permeability, and subcutaneous injection is also a kind of administering mode.
For PD0325901 of the present invention, can by itself and suitable pharmaceutically acceptable carrier coupling.This kind of pharmaceutical composition contains the compound and pharmaceutically acceptable carrier or excipient for the treatment of effective dose.This kind of carrier comprises (but being not limited to): saline, buffer, glucose, water, glycerol, ethanol and combination thereof.Pharmaceutical preparation should match with administering mode.PD0325901 of the present invention can be made into injection form, such as, be prepared by conventional method with normal saline or the aqueous solution containing glucose and other adjuvant.The medicine of such as Tablet and Capsula and so on, is prepared by conventional method.Medicine such as injection, oral liquid, Tablet and Capsula should aseptically manufacture.The dosage of active component is treatment effective dose, such as every day about 1 microgram/kg body weight-Yue 5 mg/kg body weight.In addition, PD0325901 of the present invention also can use together with other treatment agent.
When PD0325901 of the present invention is used as medicine, when the PD0325901 for the treatment of effective dose can be applied to animal tumor Experiment on therapy, wherein this treatment effective dose is usually at least about 20 micrograms/kg body weight, and be in most of the cases no more than about 25 mg/kg body weight, when clinical I phase Tumor Assays, dosage in 2 mg/day to being greater than 20 mg/day.Certainly, for the therapeutical effect with osteoarthritis of this compound, drug dose needs to re-start clinical trial.Concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Compared to the prior art, the present invention has following beneficial effect: PD0325901, as the treatment potential drug of tumor, chondrocyte is tested, Late Cambrian its have and reverse effect of cartilage degeneration, to the protective effect of chondrocyte regression.Under the effect of IL-1 β and TNFa, the topmost matrix component in chondrocyte, as Col2a1 and GAG, significantly degrade, and PD0325901 can reverse the regression effect that causes of inflammatory cytokine, makes the cellular-restoring of regression to Normocellular gene expression.In the research of Chinese medicine, do not find that other medicines have this effect so far, it is clear and definite that this medicine has therapy target, composition is single, easy to control on dosage, if can be used for the treatment of osteoarthritis, huge economic benefit will be produced, and improve the life quality of Human Osteoarthritis.
Accompanying drawing explanation
Fig. 1 is that in the embodiment of the present invention 1, protein quantification detects the result schematic diagram of (Western blot method).
Fig. 2 is the result schematic diagram of the assay of glycosaminoglycan (GAG) in the embodiment of the present invention 1.
Fig. 3 is the result schematic diagram of external Femoral cardlage tissue culture experiments in the embodiment of the present invention 2.
Detailed description of the invention
Below in conjunction with drawings and Examples, the present invention is further detailed explanation.Following examples are only not used in for illustration of the present invention and limit the scope of the invention.The experimental technique of unreceipted actual conditions in embodiment, usually conveniently condition, or according to the condition that manufacturer advises.
Embodiment 1
1. take out the SD rat extremities joint place cartilage of raw 24h, extract chondrocyte.First generation cell after going down to posterity is studied.
2. cell is divided into 5 groups: be respectively matched group, IL-1 β group (50ng/ml, peprotech company), IP0.1 group [IL-1 β+PD0325901 (0.1 μM)], IP0.25 group [IL-1 β+PD0325901 (0.25 μM)], IP0.5 group [IL-1 β+PD0325901 (0.5 μM)], TNFa group (50ng/ml, peprotech company), TP0.1 group [TNFa+PD0325901 (0.1 μM)], TP0.25 group [TNFa+PD0325901 (0.25 μM)], TP0.5 group [TNFa+PD0325901 (0.5 μM)].Wherein, PD0325901 is purchased from santacruz company.Add above drug level and cytokine respectively.After 24 hours, extract total protein of cell, carry out protein quantification detection (Western blot method) MMP13 (santacruz company, article No. SC-30073), Col2a1 (santacruz company, article No. SC-52658) and detect the content of glycosaminoglycan in cell.
3. protein quantification detects (Western blot method), the results are shown in Figure 1, chondrocyte is after IL-1 β and TNFa acts on 24 hours, the expression of MMP13 significantly improves, and the expression of Col2a1 significantly reduces, and shows cartilage generation regression, IL-1 β and TNFa respectively with the drug synergism of variable concentrations after, the expression of MMP13 is suppressed, and the expression of Col2a1 will increase, and the expression of these two albumen will return to the level (matched group) of normal chondrocyte.Further illustrate PD0325901 medicine by suppressing the expression of MMP13, thus protection cartilage matrix Col2a1 avoids it to degrade.
4. the assay of glycosaminoglycan (GAG) is according to test kit (Biocolor company, Britain).Get 100,000 chondrocyte surveys its GAG content.Chondrocyte is in IL-1 β and TNFa effect 24 with after 48 hours, the content of GAG declines, show cartilage generation regression, IL-1 β and TNFa respectively with the drug synergism of variable concentrations after, the content of GAG is improved, even the level of the normal chondrocyte of horizontal exceeding matched group of GAG, the results are shown in Figure 2.#P<0.05 and * P<0.05 compares with matched group and IL-1 β group respectively.
Embodiment 2
Take out the SD rat femur head (the now non-calcification of femoral head, is cartilaginous tissue) in raw 2 week age.Be divided into 5 groups: be respectively matched group (con group), IL-1 β group (50ng/ml, peprotech company), IP0.1 group [IL-1 β+PD0325901 (0.1 μM)], TNFa group (50ng/ml, peprotech company), TP0.1 group [TNFa+PD0325901 (0.1 μM)].Wherein, PD0325901 is purchased from santacruz company.Add above drug level and cytokine respectively.Within every 48 hours, change liquid once, to 96 hours, take out femoral head, 4% paraformaldehyde fixed more than 24 hours, carries out decalcification and dehydration, organization embedding and paraffin section.
In vitro in Femoral cardlage tissue culture experiments, find at IL-1 β group (50ng/ml, peprotech company) and TNFa group (50ng/ml, peprotech company) inflammatory factor effect 4 days, occur significantly to degenerate compared to matched group (con group) Femoral cardlage surface, glycosaminoglycan content in toluidine blue and the fast green uniform dyeing tissue of Zang Hong, the fast green dyeing of Zang Hong, dye as RED sector represents the cartilage of non-regression, the part that dyeing is green represents the cartilage of regression, Toluidine blue staining, the part of light dye is the cartilaginous areas of regression, two kinds of coloration results are all consistent.Adding after medicine PD0325901 and cytokine act on simultaneously, medicine PD0325901 can stop the regression effect that causes (see Fig. 3) of cytokine completely.
Claims (5)
1. the application of following structural formula (I) compound in preparation treatment osteoarthritis drugs
2. apply as claimed in claim 1, it is characterized in that, described structural formula (I) compound has the expression of the MMP13 suppressing IL-1 β and TNFa induction, improves the function of II Collagen Type VI and glycosaminoglycan expression simultaneously.
3. apply as claimed in claim 1, it is characterized in that, described treatment osteoarthritis drugs contains structural formula (I) compound of pharmaceutical effective amount and pharmaceutically acceptable carrier.
4. apply as claimed in claim 1, it is characterized in that, described medicine is made into the pharmaceutically acceptable dosage form of any one.
5. apply as claimed in claim 4, it is characterized in that, the pharmaceutically acceptable dosage form of described any one comprises tablet, capsule, granule, oral liquid, injection.
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| CN201510270396.6A CN104906081A (en) | 2015-05-25 | 2015-05-25 | Application of compound in preparation of osteoarthritis therapeutic drug |
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| CN201510270396.6A CN104906081A (en) | 2015-05-25 | 2015-05-25 | Application of compound in preparation of osteoarthritis therapeutic drug |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1446197A (en) * | 2000-07-19 | 2003-10-01 | 沃尼尔·朗伯公司 | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
| CN101445791A (en) * | 2008-12-04 | 2009-06-03 | 北京大学 | Method for screening pluripotent cell and special culture medium thereof |
| WO2010108126A2 (en) * | 2009-03-19 | 2010-09-23 | Fate Therapeutics, Inc. | Reprogramming compositions and methods of using the same |
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2015
- 2015-05-25 CN CN201510270396.6A patent/CN104906081A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1446197A (en) * | 2000-07-19 | 2003-10-01 | 沃尼尔·朗伯公司 | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
| CN101445791A (en) * | 2008-12-04 | 2009-06-03 | 北京大学 | Method for screening pluripotent cell and special culture medium thereof |
| WO2010108126A2 (en) * | 2009-03-19 | 2010-09-23 | Fate Therapeutics, Inc. | Reprogramming compositions and methods of using the same |
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