Indolinone compound and application thereof in myocardial injury

An indolinone, myocardial injury technology, applied in the field of compound application, can solve the problems of low membrane permeability, hindered development, no drug clinical treatment of heart disease, etc., and achieves repairing myocardial indicators, alleviating cardiac dysfunction, and protecting myocardium. damage effect

Pending Publication Date: 2022-04-05
NANJING RAYGEN HEALTH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since KN-93 can also directly inhibit the potassium current IKr and other voltage-gated potassium channels, as well as the low membrane permeability and poor bioavailability of AIP, hinder their further development in the clinic
Therefore, although CaMKII is considered as a promising therapeutic target for heart disease, so far, no drug targeting CaMKII is available for clinical treatment of heart disease.

Method used

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  • Indolinone compound and application thereof in myocardial injury
  • Indolinone compound and application thereof in myocardial injury
  • Indolinone compound and application thereof in myocardial injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of compounds shown in embodiment 1, formula S5-S10

[0036] The synthetic route of compound shown in formula S5-S10 is as follows:

[0037]

[0038] Among them, R 1 , R 2 represent the corresponding substituents in compounds S5-S10, respectively. The substituent structure of each compound involved in the synthetic route is as shown in table 1:

[0039] Substituent structure of different compounds in table 1

[0040]

[0041] The concrete synthetic method of compound S5-S10 (being compound 8) is as follows:

[0042] Synthesis of compound 3: To compound 1 (15.0 mmol) in anhydrous THF (15 ml) was added 5 ml of compound 2 (18 mmol) in ether, refluxed and stirred for 8 hours. Diluted with saturated ammonium chloride (20ml) followed by extraction three times with ethyl acetate (30ml), the combined organic layers were extracted with water and brine, dried over sodium sulfate. After vacuum concentration, the extract was purified by silica gel column chroma...

Embodiment 2

[0047] Embodiment 2, the in vitro inhibition of calcium / calmodulin kinase II activity experiment of the compound shown in formula S1-S10

[0048] 1. Experimental materials

[0049] ADP-GLO kinase activity detection kit (Promega, V6930), substrate (Biorbyt, orb364283), CaM (sigma, C4874), Caspase- Assay (Promega, G8981), KN-93 (selleck, S6787), MgCl 2 , CaCl 2 and other organic reagents were purchased from Sinopharm Group.

[0050] 2. Experimental method

[0051] 1) Screening compound concentration: In the initial screening, the compound was selected at an initial concentration of 10 μM; in the second screening, the lead compound was set in a concentration gradient, 8 gradients, and 5-fold gradient dilution.

[0052] 2) Prepare protein kinase: CaMKII-δ9 pure protein is diluted 30 times with 10mM DTT-Tris buffer.

[0053] 3) Preparation of reaction buffer: Taking the 1mL system as an example, the addition amount of each reagent and the final concentration of the reaction s...

Embodiment 3

[0066] Example 3. Effects of compounds represented by formulas S1-S10 on mice with acute myocardial ischemia-reperfusion injury

[0067] 1. Experimental materials

[0068] Eight-week-old C57 / 6J male mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

[0069] 2. Experimental method

[0070] Male healthy C57 / 6J male mice, 25±4g, were used for experiments after adaptive feeding for one week, and were randomly divided into 11 groups (Control, S1-S10), with 8 mice in each group. The mice in each group were injected intraperitoneally with 100 μL of 500 ng / ml compound solution (equivalent to 2.5 μg / kg), and the control group was given the same amount of normal saline. Myocardial ischemia / reperfusion modeling was performed 1 hour after administration, and mice were subjected to 30 minutes of cardiac ischemia followed by 24 hours of reperfusion as follows.

[0071] 1) C57 / 6J, 6-week-old male mice were randomly selected and injected intraperitonea...

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Abstract

The invention relates to the field of compound application, and discloses an indolinone compound and application thereof in myocardial injury. As a calcium / calmodulin kinase II inhibitor, the indolinone compound and the pharmaceutical salt thereof have an improvement effect on myocardial cell death, and can effectively reduce myocardial infarction areas of myocardial ischemia reperfusion mice, myocardial infarction mice and heart failure mice, repair myocardial indexes and relieve cardiac dysfunction. Inhibitors and drugs prepared from the indolinone compound and the pharmaceutical salt thereof have no toxic or side effect and have a remarkable treatment effect.

Description

technical field [0001] The invention relates to the application field of compounds, in particular to indolinone compounds and their application in myocardial injury. Background technique [0002] Ischemic heart disease has become the leading cause of death worldwide. Cardiomyocyte death plays a key role in a variety of cardiac diseases, including ischemic heart disease. Due to the very limited self-renewal ability of cardiomyocytes in adult mammals, dead cardiomyocytes cannot be replenished by living cell division, resulting in decreased cardiac function, arrhythmia, heart failure and sudden death. Timely restoration of coronary blood flow, ie, reperfusion, is an effective approach to reduce cardiomyocyte loss from ischemic cardiac injury. However, myocardial reperfusion can lead to further damage to the heart, known as ischemia / reperfusion (I / R) injury. At present, the drug treatment of cardiac ischemia / reperfusion injury is mainly divided into the following categories: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/454A61P9/10A61P9/04
Inventor 张岩雷晓光张俊霞肖瑞平
Owner NANJING RAYGEN HEALTH CO LTD
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