CN109045016A - Alleviate the method for glucocorticoid side effect - Google Patents
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Abstract
The present invention relates to a kind of application of native compound in terms of alleviating glucocorticoid side effect.
Description
Technical field
The present invention relates to a kind of application of native compound in terms of alleviating glucocorticoid side effect.
Background technique
From P.Hench, E.Kendall and T.Reichstein in 1949 for the first time in Annals of the rheumatic
It has been reported on diseases magazine since treating rheumatic arthritis with glucocorticoid medicine, glucocorticoid medicine
Inflammation, autoimmune disease and organ is clinically widely used in its excellent anti-inflammatory activity and immunosuppressive action to move
In plant.Have been reported that and show in the U.S. there are about the long-term treatment that 1% population is receiving glucocorticoid, in community-based population into
The ratio of row oral glucocorticoid treatment (wherein 65% is women) between 0.5%-0.9%, and the ratio was at >=50 years old
Women population in then be up to 2.7%；In covering 10 national osteoporosis of female researchs, daily follow-up
There are about the treatments that 4.6% women is receiving glucocorticoid in 60393 post-menopausals.At present clinically using sugar
The main reason for corticosteroid therapy includes inflammatory, rheumatic disease (such as rheumatic arthritis, polymyalgia), respiratory system disease
Sick (asthma, chronic obstructive pulmonary disease) etc..Although glucocorticoid medicine has good pharmacological activity and clinically
It is widely used, but its side effect after prolonged application should not be underestimated.
The side effect of glucocorticoid medicine is mainly manifested in following several respects: 1) fat and Cushing syndrome；(2) press down
Hypothalamus-pituitary-adrenal axis function processed；(3) hyperlipidemia and hyperglycemia；(4) to the influence of cardiovascular system；(5) to maincenter
The influence of nervous system；(6) osteoporosis and osteonecrosis.In addition, glucocorticoid can influence the catabolism of skeletal muscle and most
Lead to myopathy eventually.And oral glucocorticoid treatment about will increase patient and upper gastrointestinal bleeding occur or perforates twice of event
Risk.Therefore, clinically the non-steroidal anti-inflammatory drugs such as oral glucocorticoid and aspirin should be avoided to use simultaneously as far as possible.Capsule afterwards
Lower cataract is also a kind of one of adverse reaction after for a long time with glucocorticoid treatment, this disease and diabetes relationship
It is close but not age-related；In addition, the generation of cortical cataract is also related with the use of glucocorticoid.
The cellular elements signal transduction mechanism that glucocorticoid medicine participates in is related to arresting cell cycle and Inhibit proliferaton
Effect, specifically include inhibit Cyclin A expression, lower cyclin CDK2,4,6, Cyclin D1, c-
Myc, E2F-1 are horizontal, promote expression and activation p53 of cell cycle dependant inhibitor p21, p27 etc..It has now been found that and more relates to
And the molecule mechanism of glucocorticoid medicine, so that the drug that targetedly exploitation reduces its side effect still has clinic
Demand.
The present inventor passes through creative work, it was found that the compounds of this invention is mitigating glucocorticoid medicine
Molecular mechanism of action in terms of side effect has important clinical meaning for developing new drug.
Summary of the invention
On the one hand, the drug the present invention relates to compound shown in Formulas I in terms of glucocorticoid side effect is alleviated in preparation
In purposes:
On the one hand, the present invention relates to the treatment methods for alleviating glucocorticoid side effect, and the method includes to tested
Person applies compound or its pharmaceutically acceptable salt or ester or its pharmaceutically acceptable prodrug shown in a effective amount of Formulas I.
According to any preceding aspect, the alleviation glucocorticoid side effect is realized by adjusting Runx2 expression, preferably logical
It crosses promotion Runx2 expression to realize, especially promotes Runx2 expression to realize in the presence of glucocorticoid, such as pass through promotion
Runx2mRNA expression, or promote the protein expression of Runx2.
According to any preceding aspect, the alleviation glucocorticoid side effect is by adjusting Osteopontin (OPN) albumen
Expression is realized, preferably by promoting OPN protein expression to realize, especially promotes OPN protein expression in the presence of glucocorticoid
It realizes.
According to any preceding aspect, the alleviation glucocorticoid side effect is by alleviating JNK caused by glucocorticoid
Signal path inhibits to realize, is preferably realized by increasing the phosphorylation level of JNK, especially increased in the presence of glucocorticoid
The phosphorylation level of JNK is realized.
According to any preceding aspect, glucocorticoid side effect is selected from: fat and Cushing syndrome, Hypothalamus-pituitary-kidney
Upper gland s function inhibition, depression, amnesia, hyperlipidemia, hyperglycemia, disease of cardiovascular system, skeletal muscle catabolism,
Osteoporosis, caput femoris necrosis, Osteoblast Differentiation inhibition, hemorrhage of digestive tract, cortical cataract.
According to any preceding aspect, glucocorticoid be selected from prednisone, meprednisone, betamethasone, beclomeasone propionate,
Prednisolone, hydrocortisone, dexamethasone.
On the one hand, the present invention relates to compounds shown in Formulas I expresses in preparation for treating Runx2 caused by dexamethasone
Inhibit the purposes in the drug of related disease.
On the one hand, it is logical for treating JNK signal caused by dexamethasone in preparation that the present invention relates to compounds shown in Formulas I
Road inhibits the purposes in the drug of related disease.
According to any preceding aspect, the disease is selected from fat and Cushing syndrome, hypothalamus-pituitary-adrenal axis function
Energy inhibition, depression, amnesia, hyperlipidemia, hyperglycemia, disease of cardiovascular system, the catabolism of skeletal muscle, sclerotin are dredged
Pine, caput femoris necrosis, Osteoblast Differentiation inhibition, hemorrhage of digestive tract, cortical cataract.
On the one hand, it is thin by the skeletonization of induced by dexamethasone for alleviating in preparation that the present invention relates to compounds shown in Formulas I
Born of the same parents' Mineral nodules form the purposes in the drug suppressed.
On the one hand, the present invention relates to compounds shown in Formulas I to prepare the use in the drug for adjusting Runx2 expression
On the way, the expression of Runx2 is preferably increased, especially promotes Runx2 expression in the presence of glucocorticoid.
On the one hand, the present invention relates to compounds shown in Formulas I to prepare for adjusting Osteopontin (OPN) albumen table
The purposes in drug reached, preferably raising OPN protein expression, especially promote OPN protein expression in the presence of glucocorticoid.
On the one hand, the present invention relates to compounds shown in Formulas I to prepare the use in the drug for adjusting JNK signal path
On the way, the phosphorylation level of JNK is preferably increased, the phosphorylation level of JNK is especially increased in the presence of glucocorticoid.
On the one hand, the present invention relates to treatment Runx2 expression inhibiting related diseases, Osteopontin (OPN) protein expression
Related disease, JNK signal path is inhibited to inhibit the method for related disease, the method includes applying a effective amount of to subject
Compound shown in invention Formulas I.
According to any preceding aspect, the disease is selected from fat and Cushing syndrome, hypothalamus-pituitary-adrenal axis function
Energy inhibition, depression, amnesia, hyperlipidemia, hyperglycemia, disease of cardiovascular system, the catabolism of skeletal muscle, sclerotin are dredged
Pine, caput femoris necrosis, Osteoblast Differentiation inhibition, hemorrhage of digestive tract, cortical cataract.
Detailed description of the invention
Fig. 1: formula Compound I inhibits in the effect of MC3T3-E1 cell Osteoblast Differentiation in dexamethasone to Runx2 base
Because expression influence (* * P < 0.01vs OM,#P < 0.05,##P<0.01vs Dex)；OM: induction group；Dex: Dexamethasone group；
AF: formula Compound I group.
Fig. 2: formula Compound I inhibits in the effect of MC3T3-E1 cell Osteoblast Differentiation in dexamethasone to Runx2 (A)
With the influence of OPN (B) protein expression (* * P < 0.01vs OM,#P<0.05,##P<0.01vs Dex)；OM: induction group；Dex: ground
Sai meter Song group；AF: formula Compound I group.
Fig. 3: formula Compound I inhibits in the effect of MC3T3-E1 cell Osteoblast Differentiation in dexamethasone to JNK signal
Pathway protein expression influence (* * P < 0.01vs OM,#P<0.05vs Dex)；OM: induction group；Dex: Dexamethasone group；AF:
Formula Compound I group.
Fig. 4: formula Compound I inhibited MC3T3-E1 cell mineralising to form reduction dexamethasone at culture 14 days
Protective effect (* * P < 0.01vs OM,##P<0.01vs Dex)；OM: induction group；Dex: Dexamethasone group；AF: formula Iization
Close object group.
Fig. 5: formula Compound I inhibited MC3T3-E1 cell mineralising to form reduction dexamethasone at culture 21 days
Protective effect (* * P < 0.01vs OM,#P<0.05,##P<0.01vs Dex)；OM: induction group；Dex: Dexamethasone group；AF: this
Invention compound of formula I group.
Specific embodiment
Term " pharmaceutically acceptable salt or ester " indicates the inorganic and organic acid of the relative nontoxic of formula Compound I
Addition salts or ester and base addition salts.These salt or ester can be prepared in situ in the final separation and purification process of compound.It is special
It is not, it can be by reacting the compound of the free alkali form of purifying with the organic or inorganic acid for being suitable for, and it will be such
The salt or ester of formation separate, to prepare acid-addition salts or ester.Exemplary acid addition salts include hydrobromate, hydrochloride, sulfate,
Disulfate, phosphate, nitrate, acetate, oxalates, valerate, oleate, palmitate, stearate, lauric acid
Salt, borate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinic acid
Salt, tartrate, naphthylate, mesylate, gluceptate, Lactobionate (lactiobionate), sulfamic acid
Bis--b- the Hydroxynaphthoates of salt, malonate, salicylate, propionate, methylene-, gentisate, different thiosulfate, two
Toluoyl tartrate, mesylate, esilate, benzene sulfonate, tosilate, cyclohexyl-n-sulfonate and Kui
Buddhist nun's hydrochlorate lauryl sulfonate (quinateslaurylsulphonate) etc. (see, for example, Berge et al.,
" Pharmaceutical Salts ", J.Pharm.Sci., 66:1-9 (1977) and Remington ' s Pharmaceutical
Sciences, the 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418, accordingly entirely through
It is incorporated herein by reference).It can also be anti-by the compound and suitable organic or inorganic alkali that independently carry out making the sour form of purifying
It answers, and the salt that separation is thusly-formed, to prepare base addition salts.Base addition salts include pharmaceutically acceptable metal salt and amine salt.
Suitable metal salt includes sodium, potassium, calcium, barium, zinc, magnesium and aluminium salt.Sodium and sylvite are preferred.Suitable inorganic base addition salts be by
Metal base preparation, the metal base includes sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, hydroxide
Lithium, magnesium hydroxide and zinc hydroxide.Suitable amine base addition salts are prepared by amine, and the amine has enough alkalinity to be formed
Stable salt, and preferably include due to its medicinal hypotoxicity and acceptable and those of commonly use amine in medical chemistry,
The example of the amine includes ammonia, ethylenediamine, N- methyl-glucamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl
Ethylenediamine, chloroprocanine, diethanol amine, procaine, N- benzyl-1-phenylethylamine, diethylamine, piperazine, three (hydroxymethyl)-ammonia
Methylmethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, four
Methyl ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, ethamine, basic amino acid such as lysine and arginine, dicyclohexyl
Amine etc..
The term as used herein " pharmaceutically acceptable prodrug " indicates the prodrug of compound that can be used according to the invention,
And in the conceived case, the zwitterionic form of the compounds of this invention, the prodrug, in reasonable medical judgment scope
It is interior, unsuitable toxicity, stimulation, allergic reaction etc. are contacted without suitable for the tissue with people and lower animal, and it is reasonable
Interests/risk-ratio match, and be effective to expected use.Term " prodrug " expression converts rapidly in vivo, such as
By hydrolyzing in blood, the compound of above formula parent compound is generated.It can be converted rapidly by internal metabolic cleavage
Functional group forms a kind of group reacted with the carboxyl of the compounds of this invention.The functional group includes, but are not limited to such as alkane acyl
Base (such as acetyl group, propiono, bytyry etc.), unsubstituted and the aroyl (such as benzoyl and the substituted benzene that replace
Formoxyl), alkoxy carbonyl such as ethoxy carbonyl), trialkylsilkl (such as trimethyl and triethylsilyl), with
This kind of groups such as the monoesters (such as succinyl group) that dicarboxylic acids is formed.Due to the metabolizable cracking of the useful compound of the present invention
Group is easy to be cleaved in vivo, so the compound for carrying such group can be used as prodrug.Carry metabolism cleavable base
The compound of group has the advantages that the bioavilability that can show to improve, the advantage are to be metabolized cleavable base due to existing
It rolls into a ball and gives the solubility of parent compound raising and/or the result of absorptivity.Following documents provide discussing for prodrug:
Design of Prodrugs, H.Bundgaard are edited, Elsevier (1985)；Methods in Enzymology,
K.Widder et al. editor, Academic Press, 42,309-396 (1985)；A Textbook of Drug Design
And Development, Krogsgaard-Larsen and H.Bundgaard are edited, the 5th chapter；"Design and
The 113-191 pages of Prodrugs " of Applications of (1991)；Advanced Drug Delivery Reviews,
H.Bundgard, 8, the 1-38 pages (1992)；Journal of Pharmaceutical Sciences, 77:285 (1988)；
Nakeya et al., Chem.Pharm.Bull., 32:692 (1984)；Higuchi et al., " Pro-drugs as Novel
Volume 14 and Bioreversible carrier in Drug of Delivery Systems ", A.C.S.Symposium Series
Design, Edward B.Roche are edited, American Pharmaceutical Association and Pergamon
Press (1987), above-mentioned document are incorporated herein by reference in their entirety.
The example of prodrug includes but is not limited to acetic acid esters (salt), the formic acid of the pure and mild amine functional group in the compounds of this invention
Ester (salt) and benzoic ether (salt) derivative.
Term " therapeutically effective amount " refers to that description effectively generates the amount of the compounds of this invention of required therapeutic effect.It is such
Amount usually change according to a number of factors, and it is described variation be known description provided herein those of ordinary skill can determine and
In the range of calculating.These factors include, but are not limited to: specific individual and its age, weight, height, general physical condition
It is undergone with medical treatment, used specific compound, compound is formulated in carrier therein, the application way of selected compound
Diameter, and the property and seriousness of treated illness.
Term " pharmaceutical composition " mean comprising formula (I) compound and depending on the property of method of application and dosage form extremely
Few a kind of composition selected from following pharmaceutically acceptable ingredient, comprising: carrier, diluent, adjuvant, excipient or figuration
Agent, for example, preservative, filler, disintegrating agent, wetting agent, emulsifier, suspending agent, sweetener, corrigent, flavouring agent, antibacterial agent,
Antifungal agent, lubricant and dispersing agent.The example of suspending agent includes ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydration mountain
Pears alcohol ester, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, agar and bassora gum or these substances mixture.By a variety of
Antibacterial agent and antifungal agent, such as p-hydroxybenzoate, chlorobutanol, phenol, sorbic acid etc., it can be ensured that pre- preventing microorganism
Effect.Preferably include isotonic agent, such as sugar, sodium chloride etc..By using delayed absorber, such as aluminum monostearate and bright
Glue can be such that injection type extends and absorb.Suitable carrier, diluent, solvent or excipient example include water, it is ethyl alcohol, more
First alcohol, their suitable mixture, vegetable oil (such as olive oil) and injection organic ester such as ethyl oleate.Excipient
Example includes lactose, sodium citrate, calcium carbonate, Dicalcium Phosphate.The example of disintegrating agent includes starch, alginic acid and some complex silicates
Salt.The example of lubricant includes magnesium stearate, lauryl sodium sulfate, talcum and high molecular weight polyethylene glycol.
Term " pharmaceutically acceptable " means within the scope of reasonable medical judgment, is suitable for and people and lower animal cell
Excessive toxicity, irritation, allergic reaction etc. are contacted without, and to reasonable benefit/risk than corresponding.
Term " pharmaceutically acceptable dosage form " means the dosage form of the compounds of this invention, including such as tablet, dragee, dissipates
Agent, elixir, syrup, liquid preparation (including suspension, spray, sucking tablet, pastille, emulsion, solution, granule, glue
Wafer and suppository) and for injection liquid preparation, including Liposomal formulation.It generally can be in Remington ' s
Pharmaceutical Science, Mack Publishing Co., Easton, PA have found preparation technique and system in latest edition
Agent.
The compound of the present invention can be prepared according to various well known methods, be not particularly limited.
Embodiment of the present invention is described in detail below in conjunction with embodiment.Those skilled in the art will manage
Solution, the following examples are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Agents useful for same or instrument are not infused
Bright production firm person, being can be with conventional products that are commercially available.
Embodiment
1 formula Compound I of embodiment inhibits in the effect of MC3T3-E1 cell Osteoblast Differentiation in dexamethasone to skeletonization
The influence of related gene
MC3T3-E1 cell is grouped inoculated and cultured
(1) after cell culture to convergence degree 80%, by cell dissociation, postdigestive cell α-MEM complete medium system
For at uniform single cell suspension, cell density is made to be adjusted to 105A/hole；6 orifice plates are taken, every hole is inoculated with 2ml cell suspension, puts
Enter and is cultivated in carbon dioxide incubator.
(2) packet transaction: after planting plate for 24 hours, cell growth reaches 80%~90% convergence degree, and cell is grouped, and 3 holes/
Group replaces corresponding culture medium, the hole 2ml/ every other day.It is grouped as follows:
1. OM induces liquid α-MEM culture processing group, (OM induces liquid composition are as follows: 10mM sodium β-glycerophosphate, 50 μ g/ml dimension life
Plain C)
②10-6M Dex+OM induces liquid α-MEM to cultivate processing group
3. 10 μM of formula Compound Is+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
4. 20 μM of formula Compound Is+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
(3) cell packet transaction after culture to third day, extracts cell total rna with Trizol method.
(4) RNA Quality Identification and quantitative: after the zeroing of nanodrop instrument, the RNA sample that takes l μ l-1.5 μ lDEPC water to dissolve
Product are added on nanodrop instrument well, read OD260/280 value and RNA concentration；OD260/280 should 1.8-2.0 it
Between.
(5) reverse transcription synthesizes cDNA: pressing PrimeScriptTMRT reagent Kit with gDNA Eraser
(Perfect Real Time) Reverse Transcriptase kit specification carries out reverse transcription reaction.
(6) real-time fluorescence quantitative PCR reacts
1. design of primers
2. real-time fluorescence quantitative PCR reacts:
According to SYBR Premix Ex Taq II (Tli RNaseH Plus) specification and Thermal Cycler
DiceTMThe operating method of Real Time System amplification instrument.
Using beta-actin as internal reference, using 2-ΔΔCtRelative quantification method detects the relative expression quantity of each group gene mRNA.
Real-time fluorescence quantitative PCR is as the result is shown: compared with induction group, Dexamethasone group cell Bone formation-related gene
The expression of Runx2mRNA is lowered, and formula Compound I can restore the Runx2mRNA of dexamethasone inhibition to a certain extent
It expresses (Fig. 1)
2 formula Compound I of embodiment is in inhibiting the effect of MC3T3-E1 cell Osteoblast Differentiation to skeletonization GAP-associated protein GAP
The influence of expression and influence to JNK signal path.
(1) cell is grouped: after planting plate for 24 hours, cell growth reaches 80%~90% convergence degree, and cell is grouped, and 3 holes/
Group replaces the hole corresponding culture medium 2ml/ every other day.It is grouped as follows:
1. OM induces liquid α-MEM to cultivate processing group
②10-6M Dex+OM induces liquid α-MEM to cultivate processing group
3. 10 μM of formula Compound Is+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
4. 20 μM of formula Compound Is+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
(2) the 5th day extraction total protein of cell of cell grouping culture.
(3) determination of protein concentration (BCA method).
(4) protein example and Marker pre-treatment: from -80 DEG C of taking-up protein examples, ice bath melts；Before loading,
5x albumen sample-loading buffer is added in protein sample and adjusts each protein sample to same protein content；Be vortexed concussion 30s, centrifugation
Several seconds；Protein example and the 1x sample-loading buffer of applied sample amounts is waited to be denaturalized 5min at 95 DEG C simultaneously, is taken at once after the completion of denaturation
It is inserted into ice chest out；High speed refrigerated centrifuge, 12000rpm are centrifuged 5min；4 DEG C spare, -80 DEG C of storages.
(5) protein immunoblot experiment.
Western-blot experimental result is shown: compared with induction group, Dexamethasone group significantly suppresses skeletonization correlation mark
Remember the expression of albumen Runx2, OPN.Formula Compound I can restore Runx2 and OPN protein expression caused by dexamethasone
It lowers (Fig. 2A, Fig. 2 B).
Western-blot experimental result is shown: compared with induction group, under the ratio of Dexamethasone group p-JNK/JNK is obvious
Drop indicates that the activation of JNK signal path is suppressed.After the formula Compound I of various dose is added, with dexamethasone
Group is compared, and the ratio of dosing group p-JNK and JNK rise while concentration dependent is presented, and shows that formula Compound I can be one
Determine to alleviate the activation of JNK signal path caused by dexamethasone suppression (Fig. 3) in degree.
3 formula Compound I of embodiment inhibits MC3T3-E1 cell mineralising to form reduced protection work dexamethasone
With.
(1) postdigestive cell cell inoculation culture: is prepared into uniformly unicellular hang with α-MEM complete medium
Liquid makes cell density be adjusted to 2.5 × 104A/hole；24 orifice plates are taken, every hole is inoculated with 500 μ l cell suspensions, is put into carbon dioxide
It is cultivated in incubator.
(2) cell packet transaction: cell kind plate for 24 hours after, cell growth reaches 80%~90% convergence degree, by cell point
Corresponding culture medium, 500 holes μ l/ are replaced in group, 4 holes/group every other day.It is grouped as follows:
1. OM induces liquid α-MEM to cultivate processing group
②10-6M Dex+OM induces liquid α-MEM to cultivate processing group
3. 10 μM of invention compound of formula I+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
4. 20 μM of invention compound of formula I+10-6M Dex+OM induces liquid α-MEM to cultivate processing group
Packet transaction culture carries out Alizarin red staining and Mineral nodules quantitative detection to it to after the 14th, 21 day.Alizarin red
Coloration result shows: compared with induction group, the Alizarin red staining of Dexamethasone group obviously shoals, and with formula I chemical combination
The increase of object concentration, Alizarin red staining are gradually deepened.Mineral nodules quantitative result shows (Fig. 4, Fig. 5): compared with induction group, ground
The Mineral nodules formation of Sai meter Song group is suppressed, after formula Compound I is added, with formula Compound I concentration
Increase, the formation of Mineral nodules is gradually recovered.The experimental results showed that, dexamethasone can significantly inhibit MC3T3-E1 cell above
Mineral nodules formed.And formula Compound I can alleviate the MC3T3-E1 cell Mineral nodules shape by induced by dexamethasone
At the effect suppressed.
Claims (9)
1. compound shown in Formulas I or its pharmaceutically acceptable salt or ester or prodrug alleviate glucocorticoid side effect in preparation
Purposes in the drug of aspect:
2. purposes according to claim 1, the alleviation glucocorticoid side effect by adjust Runx2 albumen or
Osteopontin (OPN) protein expression or adjust JNK signal path realize, it is preferable that by promote Runx2 albumen or
Osteopontin (OPN) protein expression or the phosphorylation level for increasing JNK are realized.
3. purposes according to claim 1 or 2, the glucocorticoid side effect is selected from: fat and Cushing syndrome, inferior colliculus
Brain-pituitary-adrenal axis function inhibitio, depression, amnesia, hyperlipidemia, hyperglycemia, disease of cardiovascular system, skeletal muscle
Catabolism, osteoporosis, caput femoris necrosis, Osteoblast Differentiation inhibition, hemorrhage of digestive tract, cortical cataract, preferably bone
The catabolism of flesh, osteoporosis, caput femoris necrosis, Osteoblast Differentiation inhibit, and more preferable osteoporosis, Osteoblast Differentiation inhibit.
4. compound shown in Formulas I is in preparation for treating Runx2 expression inhibiting related disease or JNK caused by glucocorticoid
Signal path inhibits related disease or osteoblast mineralization tubercle to form the purposes in the drug suppressed.
5. according to the purposes of any one of preceding claims, the glucocorticoid is selected from prednisone, meprednisone, times his rice
Pine, beclomeasone propionate, prednisolone, hydrocortisone, dexamethasone, preferably prednisolone, hydrocortisone, fill in rice
Pine, most preferably dexamethasone.
6. the disease is selected from fat and Cushing syndrome, Hypothalamus-pituitary-according to the purposes of any one of preceding claims
Hypothalamic pituitary adrenal axis function inhibitio, depression, amnesia, hyperlipidemia, hyperglycemia, disease of cardiovascular system, skeletal muscle decomposition generation
It thanks, the inhibition of osteoporosis, caput femoris necrosis, Osteoblast Differentiation, hemorrhage of digestive tract, cortical cataract.
7. compound shown in Formulas I is in preparation for adjusting the purposes in the drug that Runx2 is expressed.
8. compound shown in Formulas I is preparing the purposes in the drug for adjusting Osteopontin (OPN) protein expression.
9. compound shown in Formulas I is preparing the purposes in the drug for adjusting JNK signal path.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110051677A (en) * | 2019-01-11 | 2019-07-26 | 广东医科大学 | A kind of application of Gardenoside in terms of alleviating glucocorticoid side effect |
| CN112675187A (en) * | 2021-01-11 | 2021-04-20 | 东莞市人民医院 | Application of kaempferitrin in relieving side effects of glucocorticoid |
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| CN105176921A (en) * | 2015-08-06 | 2015-12-23 | 广东医学院 | Method of testing amentoflavone in preparation of bone tissue engineering seed cells |
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| CN105176921A (en) * | 2015-08-06 | 2015-12-23 | 广东医学院 | Method of testing amentoflavone in preparation of bone tissue engineering seed cells |
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| GUANGYONG CHEN 等: "Amentoflavone protects against high fat-induced metabolic dysfunction: Possible role of the regulation of adipogenic differentiation", 《INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110051677A (en) * | 2019-01-11 | 2019-07-26 | 广东医科大学 | A kind of application of Gardenoside in terms of alleviating glucocorticoid side effect |
| CN112675187A (en) * | 2021-01-11 | 2021-04-20 | 东莞市人民医院 | Application of kaempferitrin in relieving side effects of glucocorticoid |
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