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Application of amide compound in preparation of drug for treating sepsis

A technology of amide compounds and sepsis, applied in the field of application of amide compounds in the preparation of drugs for the treatment of sepsis, to achieve the effect of inhibiting cell pyroptosis

Active Publication Date: 2020-12-15
唐怡庭
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no report on the application of amide compounds in the treatment of sepsis

Method used

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  • Application of amide compound in preparation of drug for treating sepsis
  • Application of amide compound in preparation of drug for treating sepsis
  • Application of amide compound in preparation of drug for treating sepsis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Compounds inhibit primary macrophage pyroptosis induced by CTB transfection LPS activation Caspase11

[0049] 1. Experimental steps: Extract primary peritoneal macrophages from WT mice, resuspend cells in RPMI-1640 complete medium and adjust the concentration to 1×10 6 Cells / ml, 500 μl / well 24-well plate, wash the cells twice with DPBS after adhering to the wall overnight, and replace with serum-free 1640. The compounds were added to the cells at a final concentration of 5 μM and 10 μM for pre-incubation for 1 h, then the transfection reagent Cholera Toxin (CTB) 5 μg / ml+LPS 1 μg / ml (pre-incubated at room temperature for 20 min in advance) was added to stimulate the cells overnight, and the supernatant was collected for detection at 16-18 h Lactate dehydrogenase (LDH) content (to judge cell death rate) and ELISA detection (to detect pro-inflammatory cytokines IL-1α, IL-1β).

[0050] The specific experimental operation is as follows:

[0051] 1) Extract prima...

Embodiment 2

[0061] Example 2: Compounds inhibit the oligomerization of GSDMD and thereby inhibit the pyroptosis of primary macrophages

[0062]1. Experimental steps: Extract primary peritoneal macrophages from WT mice, resuspend cells in RPMI-1640 complete medium and adjust the concentration to 1×10^6 / ml, 2ml / well 6-well plate. After adhering to the wall overnight, the cells were washed twice with DPBS and replaced with serum-free 1640. Compounds were added to the cells at final concentrations of 5 μM and 10 uM for pre-incubation for 1 h, and then CTB 5 μg / ml+LPS 1 μg / ml (pre-incubated at room temperature for 20 min in advance) was added to stimulate the cells overnight. cocktail protease inhibitors and phosphatase inhibitors), lyse cell proteins on ice for 45min. Place the ice box on a shaker to ensure that the lysate fully contacts the cells. Then use a pre-cooled cell scraper to collect the cells into an EP tube, centrifuge at 13,000 g for 15 min at 4°C, and collect the supernatant a...

Embodiment 3

[0065] Example 3: Molecular docking and analog control experiments

[0066] 1. Experimental steps: through virtual screening, the compound is docked with GSDMD, and another analog is obtained through screening. The structural formula of the analog is: The binding energy of GSDMD after docking is reduced, identifying the docking active site. Among them, the 3D diagram of molecular docking of compounds and analogs with GSDMD protein is shown in Figure 4 shown.

[0067] 2. Structural analogue control experiment: the above-mentioned structural analogue was used to replace the compound in Example 1, and the pyroptosis inhibition experiment was carried out using the same method as in Example 1, and the dosing concentration was 10 μM.

[0068] 3. Experimental results: LDH detection experiment control results are as follows: Figure 5 as shown, Figure 5 Middle CON is the control group, and the addition amount of compounds and analogues in each group is 10 μM. After adding the ...

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Abstract

The invention discloses an application of an amide compound in preparation of a drug for treating sepsis. The structure of the amide compound is shown as follows: the amide compound can inhibit Caspase11 induced macrophage pyroptosis, can inhibit release of pro-inflammatory cytokines IL-1alpha and IL-1beta, and can inhibit macrophage pyroptosis by inhibiting GSDMD protein oligomerization. Therefore, the amide compound has a certain treatment effect on sepsis, and a novel treatment method and a novel treatment medicine are provided for clinical treatment of sepsis.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to the application of an amide compound in the preparation of medicines for treating sepsis. Background technique [0002] Sepsis (sepsis, also known as sepsis) is an infection-induced critical illness characterized by multiple organ failure. Its common clinical symptoms include fever, rapid breathing rate and heartbeat, and unconsciousness. Severe sepsis can lead to insufficient blood flow to supply tissues and even lead to organ failure and septic shock, seriously threatening the lives of patients. At present, treatment such as early fluid resuscitation, early use of antibiotics and organ function support has reduced the mortality rate of sepsis to a certain extent, but sepsis is still the leading cause of death in intensive care unit (ICU) patients. [0003] The pathogenesis of sepsis is very complex. In recent years, some studies have revealed a new pathogenesis of sepsis: cysteine ​...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4174A61P31/04
CPCA61K31/4174A61P31/04
Inventor 唐怡庭吕奔
Owner 唐怡庭
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