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Triazolone thiadiazole compounds capable of promoting regeneration of cardiomyocytes and pharmaceutical use thereof

A technology for thiadiazole derivatives and triazolo, which is applied in the field of preparing medicines, 3,6-disubstituted triazolone thiadiazole derivatives or their salts, can solve the problems of unknown key targets and the like, and achieve high activity , The effect of high druggability and low toxicity

Active Publication Date: 2019-10-15
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CDNG inhibits TCF / LEF-mediated gene transcription in the Wnt signaling pathway, the key targets of CDNG in the Wnt signaling pathway remain unknown

Method used

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  • Triazolone thiadiazole compounds capable of promoting regeneration of cardiomyocytes and pharmaceutical use thereof
  • Triazolone thiadiazole compounds capable of promoting regeneration of cardiomyocytes and pharmaceutical use thereof
  • Triazolone thiadiazole compounds capable of promoting regeneration of cardiomyocytes and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Synthesis of CDNG1A and CDNG1B.

[0040] A two-step synthesis method is used:

[0041] Intermediate: 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol(III) 4-amino-5-(pyridin-4-yl)-4H-1 ,24,-triazole-4-mercapto synthesis, refer to the literature JMC 2009, 52(14), 4200-4209 (including the synthesis method of compound 16):

[0042] Carbon disulfide (3.3ml, 5.5mmol) was added dropwise to a solution of KOH (3.0g, 5.5mmol) and pyridylisoniazid (3.6mmol) in ethanol (70ml). The mixture was stirred at room temperature overnight, then cooled in an ice-water bath and diluted with diethyl ether. The precipitate was filtered off, washed with diethyl ether and dried. The obtained product (1.6mmol) was dissolved in water (2ml), hydrazine hydrate (2.4mmol) was added, and the mixture was refluxed for 6hr under stirring. Then 80 ml of water was added to the reaction mixture and neutralized with concentrated hydrochloric acid, and the precipitate was filtered with water a...

Embodiment 2

[0046] Example 2: Western blotting immunoblotting method to further verify that the effect of CDNGs on the Wnt pathway is achieved by inhibiting β-catenin ( figure 2 ).

[0047] step one

[0048] Cells: mouse CGR8 embryonic stem cells

[0049] Reagents: Known Wnt pathway agonist Chir99021, CDNG1 / CDNG1A / CDNG1B; DMEM (Sigma), 10% FBS, 100 units / ml LIF, 2 mM L-glutamine, 50 μM β-mercaptoethanol, Liposome 3000 (Life Tech), protease inhibitors, RIPA cell lysate, polyacrylamide gel, nitrocellulose membrane, skim milk powder, β-catenin primary antibody (Santa Cruz Biotechnology), GAPDH primary antibody (Santa Cruz Biotechnology), HRP secondary antibody.

[0050] Experimental procedure: The monolayer of mouse CGR8 embryonic stem cells was plated in serum-free DMEM, and 10% FBS, 100 units / ml LIF, 2mM L-glutamine and 50 μM β-mercaptoethanol were added, and placed at 37°C containing 5 %CO 2 cultured in a humid incubator. Cells were seeded into 24-well plates when they were subconfl...

Embodiment 3

[0057] Example 3: Immunohistochemical analysis CDNG1A promotes the proliferation and regeneration of zebrafish cardiomyocytes.

[0058] Animals: 4-12 month old AB wild line and transgenic zebrafish Tg(cmlc2:nDsRed-nuc).

[0059] Reagents: Primary Antibody: Rabbit anti-Mef2c (Santa Cruz); Mouse anti-PCNA (Sigma); Click-iT® EdU Alexa-Fluor-488 Kit (Invirogen); Secondary Antibody Goat Anti-Mouse Alexa-Fluor-488 , Alexa-Fluor-555 goat anti-rabbit Alexa-Fluor-488, Alexa-Fluor-555 (both purchased from Invitrogen); Bouin's solution (prepared) containing 5% acetic acid, 9% formaldehyde, 0.9% picric acid (Sigma); Insoluble aniline blue dye (Fisher); G orange dye (Sigma); acid magenta dye.

[0060] Experimental procedure: Use surgical scissors to anesthetize 4-12-month-old zebrafish with anesthesia for 2 minutes, turn the belly of the fish upward under a stereomicroscope, and cut open the abdomen at the heart to expose the heart. Carefully and quickly cut off about 20% of the apex and p...

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Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a triazolone-thiadiazole compound capable of promoting regeneration of myocardial cells and a drug use of the triazolone-thiadiazole compound. The compound comprises two 3,6-bis-substituted triazolone-thiadiazole derivatives or salts thereof: a chemical structural formula is C14H15N5S, an average molecular weight is 285.37 g / Mol, and the name is 6-cyclohexyl-3-(pyridine-4-yl)-[1,2,4]triazole[3,4-b][1,3,4]thiadiazole; a chemical structural formula is C13H13N5S, an average molecular weight is 271.37g / mol, and the name is 6-cyclopentyl-3-(pyridine-4-yl)-[1,2,4]triazole[3,4-b][1,3,4]thiadiazole. An experiment result shows that the small molecular compound is a Wnt / beta-catenin signal channel inhibitor and can effectively promote the proliferation of the myocardial cells and / or restoring the damaged myocardial cells; and an integral-mode animal model experiment shows that the triazolone-thiadiazole compound is hardly toxic, has a further research and application prospect, and can be used for preparing drugs for treating and preventing the diseases such as myocardial infarction, arrhythmia, ischemic cardiomyopathy, cardiac failure and the like.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a 3,6-disubstituted triazolonethiadiazole derivative or a salt thereof, and an application thereof in preparing medicine. Background technique [0002] The heart is the first functional organ to emerge in a developing organism. Abnormalities in cardiac development and growth are hallmark events of cardiovascular disease. According to the latest statistics from the American Heart Association and the National Center for Cardiovascular Diseases in my country, cardiovascular disease is the disease that accounts for the largest proportion of all causes of death (about 40%) [0003] Heart failure is generally treated clinically with drugs, interventional and surgical treatments to improve myocardial ischemia and other general treatments. Common drugs include diuretics, angiotensin-converting enzyme inhibitors, β-blockers, digitalis drugs, aldosterone antagonists, angio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04A61K31/4439A61P9/10A61P9/04
Inventor 钟涛倪铁华谢姝颖胡海荣
Owner FUDAN UNIV
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