CN113398114B - Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine - Google Patents
Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine Download PDFInfo
- Publication number
- CN113398114B CN113398114B CN202110590092.3A CN202110590092A CN113398114B CN 113398114 B CN113398114 B CN 113398114B CN 202110590092 A CN202110590092 A CN 202110590092A CN 113398114 B CN113398114 B CN 113398114B
- Authority
- CN
- China
- Prior art keywords
- heart failure
- tet
- compound
- pharmaceutically acceptable
- myocardial
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a compound 3,7,8,4' -tetrahydroxyflavone in preparation of a medicament for treating and/or preventing cardiovascular diseases, and relates to the technical field of medicaments. The invention discloses the therapeutic effect of the compound Tet as an SGK1 inhibitor on heart failure mice for the first time, and provides experimental evidence for clinical application of Tet in treating heart failure. Therefore, the compound Tet can be used for preparing medicaments for treating and/or preventing cardiovascular diseases, particularly medicaments for resisting heart failure, and has good application and development prospects.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound 3,7,8,4' -tetrahydroxyflavone serving as an SGK1 inhibitor applied to preparation of anti-cardiovascular disease medicines.
Background
Chronic heart failure is a complex clinical syndrome with high incidence and mortality rates that has severely compromised human health, creating tremendous clinical pressure and economic costs. In the pathological link from myocardial ischemia to heart failure, there is a compensatory process of myocardial hypertrophy and fibrosis, wherein myocardial hypertrophy is a powerful compensatory reaction of the heart under long-term internal and external stimulation, the function of pumping blood is enhanced, the wall tension of the heart chamber is weakened, and when the cause of disease can not be eliminated for a long time, the function of the hypertrophic myocardium can not be maintained normally, so that the patient dies suddenly or turns to heart failure.
Currently, the treatment strategies against heart failure mainly include: chemical treatment and surgical treatment, however, have the disadvantages of high cost, certain side effects and the like, and the search for effective targets and drugs for treating heart failure is a hot spot researched by many medical workers in recent years.
For example, the renin-angiotensin-aldosterone system is an established therapeutic target for the treatment of heart failure, spironolactone and LCZ696 (a dual-effect angiotensin receptor enkephalinase inhibitor) show great potential for use. Patent document CN110240542A discloses that chromane-3,12e-double bond-15,16-dicarboxylic acid isolated from naval purroco has selective inhibitory action on β 1 subtype of epinephrine, and is expected to be a drug of β 1-adrenoceptor inhibitor for the treatment of cardiovascular diseases such as myocardial ischemia, cardiac hypertrophy, heart failure, etc.
Mitochondria is used as the most important organelle for producing cardiac muscle cells, and the stability of the functions of the mitochondria has important significance for inhibiting the further development of cardiac hypertrophy. Several studies have demonstrated that improving mitochondrial dysfunction can inhibit myocardial hypertrophy and its progression to heart failure. Patent document CN 112156091A discloses that hispidulin contained in kiwi, saussurea involucrata, snowweed, artemisia and salvia miltiorrhiza can exert protective effects on cardiac hypertrophy and heart failure by protecting mitochondrial energy production function and inhibiting mitochondrial oxidative stress.
Serum and glucocorticoid-induced protein kinase1 (SGK 1), one of the serine/threonine kinase family members, is a homologue of AKT. SGK1 is expressed in a low content in most cells, but under certain pathophysiological conditions, such as glucocorticoid or mineralocorticoid excess, inflammation caused by TGF-beta release, hyperglycemia, cell contraction, ischemia and the like, the expression of SGK1 is obviously increased. Recent studies have shown that excessive SGK1 expression and activity can lead to the pathophysiology of a variety of diseases, including hypertension, obesity, diabetes, thrombosis, stroke, fibrotic diseases, infertility, and tumor growth. SGK1 protein inhibitors are believed to play important roles in including metabolic syndrome, showing some therapeutic prospects in the treatment of heart failure. Therefore, the search for compounds which can effectively inhibit SGK1 has potential application value.
Disclosure of Invention
The invention aims to provide an SGK1 protein inhibitor which is applied to the preparation of medicaments for resisting heart failure, particularly hypertrophic cardiomyopathy.
In order to realize the purpose, the invention adopts the following technical scheme:
the research of the invention finds that the compound 3,7,8,4' -Tetrahydroxyflavone (Tet) can inhibit the activity of SGK1 protein in a concentration-dependent manner, and the existing research shows that the overhigh activity of SGK1 protein is closely related to the occurrence and development of diseases such as hypertension, obesity, cardiovascular diseases, metabolic syndrome and the like, so the Tet has good application prospect as the SGK1 inhibitor.
The molecular formula of the compound Tet is C15H10O6CAS number 1429-28-3, the structural formula is shown in formula (I).
Furthermore, the invention takes a Phenylephrine (PE) induced myocardial cell hypertrophy model and an Isoproterenol (ISO) induced mouse heart failure model as experimental objects, and finds that the compound Tet can obviously reduce PE induced myocardial cell hypertrophy, obviously improve the ejection fraction and left ventricle shortening fraction value of the ISO induced heart failure model, improve the symptoms of chronic cardiac insufficiency and reduce the extension and expansion of collagen fibers after heart failure. Intensive mechanism research finds that the compound Tet plays a protective role in myocardial hypertrophy and heart failure by inhibiting SGK1 activity.
Therefore, the invention provides the application of the compound Tet or the pharmaceutically acceptable salt thereof in preparing the medicines for treating and/or preventing cardiovascular diseases.
Further, the cardiovascular disease is heart failure. In particular, the heart failure is a clinical syndrome in which myocardial damage progresses to a terminal ring.
Further, the heart failure manifests as myocardial hypertrophy.
The compound Tet or a pharmaceutically acceptable salt thereof can be used for reducing myocardial hypertrophy.
Further, the compound Tet or a pharmaceutically acceptable salt thereof reduces the area of collagen fibers caused by myocardial injury.
Further, the compound Tet or a pharmaceutically acceptable salt thereof inhibits the activity of serum and glucocorticoid-induced protein kinase1 (SGK 1).
The present invention also provides a pharmaceutical composition for the treatment and/or prevention of heart failure, comprising the compound Tet or a pharmaceutically acceptable salt thereof as an active ingredient.
The medicament also comprises a pharmaceutically acceptable excipient or carrier. The preparation form of the medicament is liquid preparation or solid preparation. The pharmaceutical composition can be administered by intravenous, oral, sublingual, intramuscular or subcutaneous routes, or by the skin mucosa route.
The invention has the following beneficial effects:
the invention discloses the therapeutic effect of the compound Tet as an SGK1 inhibitor on heart failure mice for the first time, and provides experimental evidence for clinical application of Tet in treating heart failure. Therefore, the compound Tet can be used for preparing medicaments for treating and/or preventing cardiovascular diseases, particularly medicaments for resisting heart failure, and has good application and development prospects.
Drawings
FIG. 1 is a dose-effect graph of different concentrations of Tet on SGK1 inhibition in example 1.
FIG. 2 is a graph showing the results of Tet's effect on the cardiomyocyte hypertrophy model in example 2 wherein the cardiomyocytes were labeled with phalloidin.
FIG. 3 is the quantitative statistics of the cardiomyocyte area under the effect of Tet on the cardiomyocyte hypertrophy model in example 2.
FIG. 4 is a representation of ultrasound of the mouse heart under the effect of Tet on the ISO-induced heart failure model in example 3.
FIG. 5 is a graph showing the effect of Tet on the cardiac function and cardiac structure of mice in the ISO-induced heart failure model in example 3, wherein A is the ejection fraction value (EF%), B is the left ventricular fractional shortening value (FS%), C is the end-diastolic left ventricular volume (LV Vol, D), D is the end-systolic left ventricular volume (LV Vol, D; LV Vol, s), E is the left ventricular end-systolic ventricular interval thickness (IVS; s), F is the left ventricular end-diastolic inner diameter (LVID; D), G is the left ventricular end-systolic inner diameter (LVID; s), H is the left ventricular end-diastolic wall thickness period (LVPW; D), and I is the left end-systolic wall thickness (LVPW; s).
FIG. 6 is a graph representing the effect of Tet on the area of mouse collagen fibers as measured by Masson staining in example 3.
FIG. 7 is a quantitative statistical result of Masson staining test Tet on the effect of mouse collagen fiber area in example 3.
Detailed Description
The spirit and advantages of the present invention will be further described with reference to the accompanying drawings and examples, which are provided for illustration only and are not intended to be limiting. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
The molecular formula of the compound Tet (3, 7,8,4' -tetrahydroxyflavanone, the Chinese name is 3,7, 8-trihydroxy-2- (4-hydroxyphenyl) -4H-1-benzopyran-4-one) is C15H10O6CAS number 1429-28-3, the structural formula is shown in formula (I). Tet standards were purchased from Calboses chemical technology.
Example 1 inhibitory Effect of Tet on SGK1 protein
50 μ L of mass spectrometry probe CKRPRAASFAE (final concentration 25 μ M), 25 μ L of SGK1 (final concentration 0.25 μ g/mL), different concentrations of Tet (final concentrations 195, 391, 781, 1560, 3130, 6250, 12500, 25000nM, respectively), 50mM Tris-HCl (pH =7.5, containing 10mM MgCl2400 μ M ATP,2mM DTT,5mM β -Glycerophorospate) to 100 μ L, incubated at 30 ℃ for 1h, then quenched by addition of 200 μ L methanol (containing 0.1% TFA), the solution vortexed, centrifuged, and the supernatant was used for sample analysis.
The analysis conditions were: an agent 1100 liquid phase-1946D single quadrupole mass spectrometer; column, zorbax SB C18 (4.6 mm. Times.250mm, 5 μm); mobile phase 0.1% trifluoroacetic acid-water (a) and 0.1% trifluoroacetic acid-acetonitrile (B); the flow rate is 0.6mL/min; an elution gradient of 0-15min,13-28% by weight B; 15-1695in, 28-100% by weight B; sample size, 30 μ L. The column temperature was 30 ℃.
As a result, tet can inhibit SGK1 activity and IC in a concentration-dependent manner, as shown in FIG. 150＝307.5nM。
Example 2 Primary suckling mouse cardiomyocyte hypertrophy model
A model of myocardial cell hypertrophy was induced using Phenylephrine (PE).
Separating primary suckling mouse cardiac muscle cells, inoculating the primary suckling mouse cardiac muscle cells into a 96-hole black transparent plate/6-hole plate, adhering to the wall for 24 hours, then replacing the primary suckling mouse cardiac muscle cells with serum-free basic culture solution, and starving for 24 hours for later use. The culture medium was discarded, the Control group was added with a new culture medium, the Model group was added with 50. Mu.M PE, and the administration group was added with Tet (12.5, 25. Mu.M) at different concentrations and 50. Mu.M PE for a combined intervention of 48 hours, to investigate the anti-myocardial hypertrophy effect of Tet.
As shown in fig. 2 and 3, tet significantly reduced PE-induced cardiomyocyte hypertrophy.
Example 3 ISO-induced mouse Heart failure model
The male C57BL/6 mice were randomly divided into 3 groups by body weight, namely, a blank Control group (Control), a heart failure Model group (Model), a Tet low-concentration administration group and a Tet high-concentration administration group, each of which was 10 mice. Model group and Tet group adopt a method of continuous subcutaneous injection ISO (5 mg/kg/day) for 3 weeks to establish a mouse heart failure Model; the Control group was injected subcutaneously with the corresponding dose of saline, the Tet administration group was simultaneously administered with Tet at different concentrations for intervention, and the Tet standard was dissolved in saline (containing 1% DMSO) and then administered intraperitoneally at doses of 10mg/kg and 20 mg/kg/day for 21 days. Mice were weighed once a day and the dose volume was adjusted in time according to the change in body weight.
And performing ultrasonic cardiac detection after modeling is finished, wherein ultrasonic detection indexes comprise: left ventricular ejection fraction (EF,%), left ventricular short axis shortening rate (FS,%), end diastole and end systole left ventricular volumes (LV Vol, d; LV Vol, s), and other cardiac function related indexes.
After the experiment, the mouse myocardial tissue is embedded, sliced and Masson stained.
The experimental results are shown in FIG. 4 and FIG. 5, tet can increase the ejection fraction (EF%) and left ventricular fractional shortening (FS%) of the rats in the model group, increase the left ventricular end-systolic ventricular space thickness (IVS; s), and increase the left ventricular end-diastolic and end-systolic wall thickness (LVPW; d, LVPW; s); reduce the end-diastolic and end-systolic left ventricular volumes (LV Vol, d; LV Vol, s), reduce the left ventricular end-diastolic and end-systolic internal diameters (LVID; d, LVID; s), and improve the symptoms of chronic cardiac insufficiency caused by ISO. Therefore, it can be used for treating heart failure.
Experimental results as shown in fig. 6 and 7, tet significantly reduced the collagen fiber area.
Claims (6)
1. The application of the compound with the structural formula shown as the formula (I) or the medicinal salt thereof in preparing the medicine for treating and/or preventing cardiovascular diseases is characterized in that the cardiovascular diseases are heart failure, and the heart failure is myocardial hypertrophy; the compound or the pharmaceutically acceptable salt thereof can inhibit the activity of protein kinase1 induced by serum and glucocorticoid so as to play a role in protecting myocardial hypertrophy and heart failure,
2. the use of claim 1, wherein the heart failure is a clinical syndrome of progression of myocardial injury to the terminal ring.
3. The use according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof reduces myocardial hypertrophy.
4. The use according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof reduces collagen fibre area as a result of myocardial injury.
5. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable excipient or carrier.
6. The use of claim 1, wherein the medicament is formulated as a liquid formulation or a solid formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110590092.3A CN113398114B (en) | 2021-05-28 | 2021-05-28 | Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110590092.3A CN113398114B (en) | 2021-05-28 | 2021-05-28 | Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113398114A CN113398114A (en) | 2021-09-17 |
| CN113398114B true CN113398114B (en) | 2022-11-01 |
Family
ID=77674876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110590092.3A Active CN113398114B (en) | 2021-05-28 | 2021-05-28 | Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113398114B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112156091A (en) * | 2020-09-30 | 2021-01-01 | 中山大学附属第一医院 | Application of hispidulin in preparation of medicine for treating and/or preventing cardiovascular diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008012909A1 (en) * | 2008-03-06 | 2009-09-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of flavonoid compounds for the prophylaxis and therapy of ischemic or inflammatory cardiovascular diseases |
| CN105560220A (en) * | 2014-10-11 | 2016-05-11 | 首都医科大学附属北京安贞医院 | Application of novel SGK1 inhibitor EMD638683 in preparation of drug used for treating acute myocardial infarction |
-
2021
- 2021-05-28 CN CN202110590092.3A patent/CN113398114B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112156091A (en) * | 2020-09-30 | 2021-01-01 | 中山大学附属第一医院 | Application of hispidulin in preparation of medicine for treating and/or preventing cardiovascular diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113398114A (en) | 2021-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2119444B1 (en) | Therapeutic agent for pain disease | |
| CN112979743B (en) | Betulinic acid derivative and application thereof | |
| CN110934873B (en) | Anti-aging drug D/S targeting aged cells in tissue microenvironment and application thereof | |
| US20170080011A1 (en) | Use of nadh and nmn in preparation of drugs or health-care products for treating parkinson's disease | |
| WO2015176539A1 (en) | Use of isoquinoline alkaloid derivative for preparing drug capable of promoting ampk activity | |
| EP2589382A1 (en) | Pharmaceutical composition comprising levocarnitine and dobesilate | |
| US20140221472A1 (en) | Use of myricetin or derivatives thereof as a cathepsin k inhibitor | |
| CN113398114B (en) | Application of 3,7,8,4' -tetrahydroxyflavone in preparing anti-cardiovascular disease medicine | |
| US10702586B2 (en) | Methods for treating diseases mediated by ErbB4-positive pro-inflammatory macrophages | |
| CN113181167B (en) | Application of curatin in preparation of medicine for treating myocardial hypertrophy | |
| CN115837023A (en) | Application of 1-methylnicotinamide in preparation of anti-vascular calcification drugs | |
| CN107913273B (en) | The application of mesaconine | |
| CN113368106B (en) | Use of etomod in medicine for preventing and treating idiopathic pulmonary fibrosis | |
| US9629866B2 (en) | Use of cordycepin in manufacture of medicaments for anti-depression | |
| KR101603279B1 (en) | Pharmaceutical composition for prevention or treatment of diseases induced by activation of NFAT5 containing protoberberine derivative or pharmaceutically acceptable salts as an active ingredient | |
| CN112999214A (en) | Use of homovanillic acid in preparing medicine for resisting platelet and thrombosis | |
| CN111407884A (en) | Application of somatotropin releasing hormone agonist GHRH-A in preparation of anti-aging drugs | |
| CN109718230A (en) | Application of the salviandic acid A in preparation inhibiting hyperuricemia and anti-gout drugs | |
| CN113304139B (en) | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs | |
| CN113582863B (en) | Aminoethyl biphenyl compound and preparation method and application thereof | |
| CN108379270A (en) | A kind of ligustrazine derivant is preparing the application in preventing and treating anti-parkinson drug | |
| CN112535682B (en) | Application of Shaerweike ketone derivative in preparation of medicine | |
| CN115317485B (en) | Application of isoliensinine and neferine in preparation of anti-hepatic fibrosis drugs | |
| CN112826820B (en) | NLRP3 inhibitor and application thereof | |
| CN118286244A (en) | Application of solasonine in preparing medicine for treating oral squamous cell carcinoma |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |