CN110483447A - 1 antagonist of Thyroid hormone receptor β and its application - Google Patents
1 antagonist of Thyroid hormone receptor β and its application Download PDFInfo
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- CN110483447A CN110483447A CN201910846644.5A CN201910846644A CN110483447A CN 110483447 A CN110483447 A CN 110483447A CN 201910846644 A CN201910846644 A CN 201910846644A CN 110483447 A CN110483447 A CN 110483447A
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- compound
- pharmaceutically acceptable
- thyroid hormone
- acceptable salt
- hormone receptor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- General Health & Medical Sciences (AREA)
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- Diabetes (AREA)
- Endocrinology (AREA)
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Abstract
The present invention provides 4 kinds of 1 antagonists of Thyroid hormone receptor β and its application, external biological experiment finds it with 1 antagonistic activity of Thyroid hormone receptor β.
Description
Technical field
The invention belongs to small-molecule drug fields, more particularly, to 4 kinds of 1 antagonists of Thyroid hormone receptor β and its application.
Background technique
Thyroid hormone is a kind of important endocrine hormone in body, is hormone secreted by thyroid gland.Thyroid gland swashs
It is known as and boosts metabolism and develop, improve the excitatoty effect of nervous system, breathing and heart rate, human body can also be made
Heat production increases.Thyroid Hormone Receptors (thyroid hormone receptors, TRs) be a kind of ligand-dependent transcriptional because
Son, in mammals it has been found that multiple and different TR hypotypes, there is TR α (thyroid hormone α receptor) and TR β (thyroid gland respectively
Hormone beta receptor).TR β gene is located at human chromosome 3p24.3, mainly includes TR β 1, TR β 2, TR β 3 and TR Δ β 3.Except TR Δ β 3
Outside, remaining is considered as functional receptor in combination with T3 and thyroid hormone DNA regulation original part.
1 antagonist of Thyroid hormone receptor β is widely used in hyperthyroidism.Hyperthyroidism is due to first
The synthesis of shape gland discharges excessive thyroid hormone, causes organism metabolism hyperfunction and sympathetic activation, cause palpitaition, perspiration, into
Food and bowel frequency increase the illness with weight loss.Most of patients also usually has the diseases such as expophthalmos, palpebral edema, hypopsia simultaneously
Shape.If hyperthyroid patient is not treated properly for a long time, hyperthyroid heart disease can be caused.Anti-thyroid drugs controls thyroid gland
Hormone secretion is excessive, can treat hyperthyroidism.In addition to by inhibiting thyroid peroxidase activity to reduce thyroid hormone synthesis,
Itself also has immunoregulation effect.Anti-thyroid drugs is to autoimmune correlation thyroid disease --- and Graves disease is drawn
The hyperthyroidism of hair not only can be reduced thyroid blood flow in addition to reducing thyroid hormone, moreover it is possible to pass through immunoregulation effect, drop
Low thyrotrophin receptor antibody is horizontal, from Graves disease pathogenesis angle is caused, realizes the mesh from source treatment hyperthyroidism
's.
Therefore, the research important in inhibiting of 1 antagonist of Thyroid hormone receptor β.
Summary of the invention
In view of this, the present invention is directed to propose 4 kinds of 1 antagonists of Thyroid hormone receptor β and its application.
In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:
The present invention provides structural formula (I-IV) compound and its pharmaceutically acceptable salt for indicating.
Entitled betulic acid is commonly used, the entitled Betulinic acid of English, No. CAS is 472-15-1, and molecular formula is
C30H48O3, molecular weight 456.700.
Entitled Isorhamnetin is commonly used, the entitled Isorhamnetin of English, No. CAS is 480-19-3, and molecular formula is
C16H12O7, molecular weight 316.262.
Commonly use entitled artemetine, English entitled 5-Hydroxy-3,3 ', 4 ', 6,7-pentamethoxyflavone, CAS
Number be 479-90-3, molecular formula C20H20O8, molecular weight 388.368.
Entitled Cephalomannine is commonly used, the entitled Cephalomannine of English, No. CAS is 71610-00-9, molecular formula
For C45H53NO14, molecular weight 831.901.
Above compound and its pharmaceutically acceptable salt are high for treating or preventing Thyroid hormone receptor β 1 in preparation
The purposes of the drug of related disease caused by expression or hyperactivity or illness.
Above compound and its pharmaceutically acceptable salt treat the purposes of hyperthyroidism disease drug in preparation.
A kind of pharmaceutical composition, including above compound and its pharmaceutically acceptable salt and its pharmaceutically acceptable tax
Shape agent.
Described pharmaceutical composition further includes pharmaceutically acceptable excipient, diluent or carrier.It is specific as syrup, I
Primary glue and starch etc..The pharmaceutical composition can by vein, it is oral, sublingual, given through muscle or subcutaneous, skin and mucosa approach
Medicine.
The dosage form of described pharmaceutical composition is liquid preparation or solid pharmaceutical preparation.Specific such as tablet, capsule and injection
Agent etc..Each dosage form can be prepared with pharmacy conventional method.
A kind of compound medicine includes above compound and its pharmaceutically acceptable salt and can be with medicine associated with it
Object.
Compared with the existing technology, 4 kinds of Thyroid hormone receptor βs of the present invention, 1 antagonist and its application have following
Advantage:
Thyroid hormone β1receptor functional experiment (the TRbeta antagonist of 4 kinds of compounds of the present invention
CAMP assay) IC50At 10 μM hereinafter, the IC of compound 472-15-150It is 2.45 μM, compound 480-19-3's
IC50It is 3.118 μM, the IC of compound 479-90-350It is 8.658 μM, the IC of compound 71610-00-950It is 0.016 μM.
Detailed description of the invention
Fig. 1 is the compounds of this invention 472-15-1 in functional experiment to the inhibiting rate curve of Thyroid hormone receptor β 1；
Fig. 2 is the compounds of this invention 480-19-3 in functional experiment to the inhibiting rate curve of Thyroid hormone receptor β 1；
Fig. 3 is the compounds of this invention 479-90-3 in functional experiment to the inhibiting rate curve of Thyroid hormone receptor β 1；
Fig. 4 is the compounds of this invention 71610-00-9 in functional experiment to the inhibiting rate curve of Thyroid hormone receptor β 1；
Specific embodiment
In addition to being defined, technical term used in following embodiment has universal with those skilled in the art of the invention
The identical meanings of understanding.Test reagent used in following embodiment is unless otherwise specified conventional biochemical reagent；It is described
Experimental method is unless otherwise specified conventional method.
The present invention relates to compound 472-15-1,480-19-3,479-90-3 and 71610-00-9 to be purchased from Chengdu moral
Si Te Bioisystech Co., Ltd.
Below with reference to embodiment, the present invention will be described in detail.
Embodiment
Experimental procedure
1, cell suspension preparation and kind plate
A) all cells are tested all in accordance with ATCC standard operation culture, HEK293T in exponential phase of growth.
B) culture medium is discarded.
C) it is cleaned cell 2 times with PBS.
D) pancreatin digestive juice vitellophag is added, is terminated and is digested with complete medium.
E) it collects cell and counts, only can just be tested when cell survival rate is greater than 90%.
F) kind 5.5*106HEK293T cell is into 100mm Tissue Culture Dish.
G) culture dish for having planted cell is placed in 37 DEG C, 5%CO2 incubator is incubated overnight.
2, cell transfecting
A) Trans-IT transfection reagent is placed into equilibrium at room temperature；
B) Trans-IT transfection reagent is added to Opti-MEMTMCulture medium is careful not to encounter tube wall, be blown with liquid-transfering gun
Persorption is even, is stored at room temperature 5 minutes；
C) 10 μ g plasmids are added into transfection reagent, is careful not to encounter tube wall, is mixed, be stored at room temperature with liquid-transfering gun pressure-vaccum
20 minutes；
Plasmid: 7.5 μ g pBIND-TR β and 2.5 μ g pGL4.35 plasmids are separately added into
D) transfection reagent of mixed DNA is added in 100mm Tissue Culture Dish；
E) culture dish is placed in 37 DEG C, 5%CO2 incubator culture 4-7h.
3, compound is handled
A) compound diluted Echo550 is shifted into 125nl (6007680-50, PE) into tissue culture plate；
B) by cell kind into 384 tissue culture plates (6007680-50, PE), every 15,000 cell number of hole, 25 μ l contain 5%
Charcoal adsorbs FBS culture medium and 0.01 μM of T3；
C) cell is incubated overnight in 37 DEG C, 5%CO2 incubator.
4, compound test
A) by Steady-GloTMDetection reagent places room temperature；
B) 384 cell plates are placed into room temperature；
C) 25 μ L Steady-Glo are added in every holeTMDetection reagent is in tissue culture plate；
D) plank is put on oscillator and is protected from light concussion 5min；
E) values of chemiluminescence is detected with Envision 2104.
Through this embodiment, it was found that four kinds of 1 antagonists of Thyroid hormone receptor β, the external suppression of compound 472-15-1
System activity is 2.45 μM, and the external inhibitory activity of compound 480-19-3 is 3.118 μM, the external inhibition of compound 479-90-3
Activity is 8.658 μM, and the external inhibitory activity of compound 71610-00-9 is 0.016 μM.
Claims (9)
1. compound and its pharmaceutically acceptable salt that structure formula (I) indicates:
2. compound and its pharmaceutically acceptable salt that structure formula (II) indicates:
3. compound and its pharmaceutically acceptable salt that structure formula (III) indicates:
4. compound and its pharmaceutically acceptable salt that structure formula (IV) indicates:
5. any one of the claim 1-4 compound and its pharmaceutically acceptable salt are in preparation for treating or preventing first shape
The purposes of the drug of related disease caused by the expression of gland β1receptor height or hyperactivity or illness.
6. any one of the claim 1-4 compound and its pharmaceutically acceptable salt are in preparation treatment hyperthyroidism disease drug
Purposes.
7. a kind of pharmaceutical composition, it is characterised in that: including any one of claim 1-4 as the active constituent compound
Or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
8. a kind of compound medicine, it is characterised in that: comprising any one of the claim 1-4 thyroid gland β1receptor antagonist and
It can be with drug associated with it.
9. pharmaceutical composition according to claim 7 is in preparation for treating or preventing the expression of thyroid hormone β1receptor height
Or the purposes of the drug of related disease caused by hyperactivity or illness.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910846644.5A CN110483447A (en) | 2019-09-09 | 2019-09-09 | 1 antagonist of Thyroid hormone receptor β and its application |
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| CN201910846644.5A CN110483447A (en) | 2019-09-09 | 2019-09-09 | 1 antagonist of Thyroid hormone receptor β and its application |
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| CN110483447A true CN110483447A (en) | 2019-11-22 |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074218A (en) * | 2006-05-19 | 2007-11-21 | 中国医学科学院药物研究所 | Cephalotamannine derivative, its production, its medicinal composition and use |
| CN105418637A (en) * | 2015-12-08 | 2016-03-23 | 彭冬青 | Pharmaceutical composition for treating hyperthyroidism |
| CN105820147A (en) * | 2016-04-29 | 2016-08-03 | 新疆维吾尔自治区药物研究所 | Preparation method and application of active ingredients of artemisia rupestris |
| CN106146449A (en) * | 2016-07-06 | 2016-11-23 | 贵州大学 | The preparation of isorhamnetin and application process thereof in sea-buckthorn pomace |
| CN106727491A (en) * | 2016-12-08 | 2017-05-31 | 河北润茂制药有限公司 | A kind of Bilobanoate medicinal raw material |
| CN107412221A (en) * | 2017-08-03 | 2017-12-01 | 西北大学 | A kind of tree peony seed extract and its application as antineoplastic |
| CN109180772A (en) * | 2018-09-05 | 2019-01-11 | 常州大学怀德学院 | A kind of preparation method of high-purity betulic acid |
-
2019
- 2019-09-09 CN CN201910846644.5A patent/CN110483447A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074218A (en) * | 2006-05-19 | 2007-11-21 | 中国医学科学院药物研究所 | Cephalotamannine derivative, its production, its medicinal composition and use |
| CN105418637A (en) * | 2015-12-08 | 2016-03-23 | 彭冬青 | Pharmaceutical composition for treating hyperthyroidism |
| CN105820147A (en) * | 2016-04-29 | 2016-08-03 | 新疆维吾尔自治区药物研究所 | Preparation method and application of active ingredients of artemisia rupestris |
| CN106146449A (en) * | 2016-07-06 | 2016-11-23 | 贵州大学 | The preparation of isorhamnetin and application process thereof in sea-buckthorn pomace |
| CN106727491A (en) * | 2016-12-08 | 2017-05-31 | 河北润茂制药有限公司 | A kind of Bilobanoate medicinal raw material |
| CN107412221A (en) * | 2017-08-03 | 2017-12-01 | 西北大学 | A kind of tree peony seed extract and its application as antineoplastic |
| CN109180772A (en) * | 2018-09-05 | 2019-01-11 | 常州大学怀德学院 | A kind of preparation method of high-purity betulic acid |
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Application publication date: 20191122 |