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Compound capable of inhibiting zinc ion metalloproteinases

A metalloprotease and compound technology, applied in the preparation of organic compounds, active ingredients of heterocyclic compounds, active ingredients of carbohydrates, etc., can solve problems such as failure of clinical tests, impact on normal physiological functions, and low specificity of inhibitors

Inactive Publication Date: 2006-09-27
房学迅
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these small-molecule drugs can effectively inhibit the activity of MMPs and effectively prevent tumor growth and metastasis in preclinical animal experiments, the results of clinical treatment of cancer are not satisfactory, which eventually led to late clinical trials. s failure
This is mainly because the complexity of the MMP family has not been fully understood, the specificity of these inhibitors is not strong, and the normal physiological functions of other types of MMPs have also been affected to varying degrees.

Method used

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  • Compound capable of inhibiting zinc ion metalloproteinases
  • Compound capable of inhibiting zinc ion metalloproteinases
  • Compound capable of inhibiting zinc ion metalloproteinases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 1,2,3-trihydroxybenzene and its derivatives have inhibitory effect on zinc ion metalloprotease

[0057] Enzyme experiment steps:

[0058] The buffer system used is 50mM HEPES (pH7.5), with 0.2M NaCl, 10mM CaCl 2 , and 0.05% Brij-35, the substrates used are DQ-Gelatin and P126; measured at room temperature, the total reaction volume is 100ml. When adding inhibitors, the enzyme and inhibitor should be incubated in the buffer system for 30 minutes, and then added to the substrate assay. All detection instruments are FLX800 fluorescence microplate reader (Bio-Tek). For DQ-Gelatin, the excitation wavelength is 495nm, the emission wavelength is 515nm, and for P126, the excitation wavelength is 328nm, and the emission wavelength is 393nm.

[0059] The measured reaction time is 8 minutes, and the slope of the line formed by the fluorescence value is taken as the velocity, and the one without inhibitor is recorded as V 0 , plus the inhibitor is V i , with V i / V ...

Embodiment 2

[0062] Example 2 Antitumor Experiment of Pyrogallic Acid

[0063] 1. Inhibition of adhesion and extension of HT1080 tumor cells by pyrogallic acid

[0064] Adhesion test:

[0065] After the HT1080 cells in the logarithmic growth phase were digested and resuspended, the cells were counted, and then counted with 10 3 The cell density per well was introduced into a 24-well plate, and a specified amount of pyrolytic acid was added to make the final concentration of the drug in each well be 0 μM, 2 μM, 5 μM, 10 μM, and 20 μM, and then 1 ml of 10% FBS was added to each well. After mixing the DMEM medium, put it in a 37°C incubator for about 30 minutes, take it out, and centrifuge it at 1000 rpm for 5 minutes with an orifice centrifuge, then suck off the supernatant, and observe the cells adhering to the bottom of the well in each well under an inverted microscope. number of cells.

[0066] Stretch test:

[0067] After the HT1080 cells in the logarithmic growth phase were digeste...

Embodiment 3

[0083] Example 3 Drug Treatment of Atherosclerosis with Specific Anti-MMP

[0084] 1. Atherosclerosis and MMPs

[0085] Atherosclerosis is the pathological basis of clinical syndromes such as acute myocardial infarction and unstable angina, and matrix metalloproteinases (MMPs) play an important role in cardiovascular remodeling by degrading extracellular matrix. The expression of MMPs is not only related to intimal thickening and plaque instability, but also related to the formation of restenotic lesions. The detected MMPs up-regulated in atherosclerosis include MMP-1, -2, -7, -9, -12. Many MMPs are related to matrix remodeling in atherosclerotic injury, such as MMP-1, -2, -3, -7, -9, -12, -13, -14. Therefore, the development of specific anti-MMP therapeutic drugs will help prevent the development of atherosclerosis, plaque rupture and restenosis.

[0086] 1. Atherosclerotic intima thickening: Atherosclerosis can be initiated by chemical or mechanical damage to the endothel...

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PUM

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Abstract

The invention discloses a 1,2,3-trihydroxy benzene and derivant or pharmacy acceptable salt for zinc ion metal-prolease inhibition, which is characterized by the following: theses compounds is used for selective depressant of zinc ion metal-prolease (such as MT1-MMP, gelatinase A, B and collagenase, matrilysins, metal-elastase and stromelysin-1); these depressants can adjust physiological and pathology course with MMPs, ADAMs, ADAM-TS such as vessel rebirth, wound healing, organ transplantation, fecundation course and reactivation capability, rebuilding bone and ache, which is used for treating cancer, cardiovascular disease, arthritis, periodontal disease, multiple sclerosis, inflammation, adenomyosis, cornea ulcer, bacterial meningitis, diabetic syndrome, kidney disease, nerve retrogression disease, AIDS, bleb, anaphylaxis, adenomyosis, osteoporosis, asthma and so on; theses blocking agents can be used for antisenescence, antibiosis, commercial manufacture addition agent of cell epimatrix, collagen product, cosmetics and make-up preparation, which can used for animals and other living bodies.

Description

technical field [0001] The invention relates to a compound capable of inhibiting zinc ion metalloprotease, its use and a pharmaceutical composition containing the compound. Background technique [0002] Matrix metalloproteinases, namely Matrix Metalloproteinases, MMPs for short, are Zn 2+ Generic term for a family of metalloendopeptidases involved in the degradation of the extracellular matrix (ECM). MMPs are a Zn 2+ Dependent protease family, mainly synthesized and secreted by fibroblasts, endothelial cells, macrophages, neutrophils, etc., usually under neutral conditions and Ca 2+ To play a role with participation, 23 kinds of human MMPs have been discovered so far. Various MMPs generally have the following characteristics: ① The cDNA sequences of different MMPs have homology. ② They are all secreted in the form of zymogens, activated by proteases or other factors, and can degrade one or more ECMs after activation. ③ Enzyme activity depends on Zn in the active center ...

Claims

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Application Information

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IPC IPC(8): C07C39/10C07C69/84C07C65/03C07D311/30C07H13/08C07H19/01C07H17/07C07C243/24C07C49/825C07C50/16A61K31/33A61K31/70A61K31/19A61K31/215A61P43/00A61P35/00A61P9/00A61P19/02A61P29/00A61P3/10A61P25/00A61P31/18A61P15/00A61P19/10A61P11/00
CPCC07C69/88C07C51/00C07C39/10C07D311/30C07C50/16C07C243/24C07C49/825A61P3/10A61P9/00A61P11/00A61P15/00A61P19/02A61P19/10A61P25/00A61P29/00A61P31/18A61P35/00A61P43/00
Inventor 房学迅姬海涛金峰海柳森牛凤兰史秀娟王会铃桑清湘曹强李惟王玉宏
Owner 房学迅
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