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Hydrazine nitrile cathepsin K inhibitor and its application in the preparation of medicines for treating osteoarthritis

A technology for cathepsin and osteoarthritis, applied in the field of cathepsin inhibitors, can solve the problems of poor reproducibility, ineffective treatment, complicated pathogenesis, etc.

Inactive Publication Date: 2017-10-27
JILIN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

The pathogenesis of OA is very complex, and there is no unified conclusion so far. [3]
The current drugs for the treatment of OA include non-steroidal anti-inflammatory drugs, glucocorticoids, and some other biological drugs (such as glucosamine, chondroitin sulfate, and hyaluronic acid, etc.), but they are also limited to symptomatic treatment, and the therapeutic effect is not obvious , poor reproducibility [4]

Method used

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  • Hydrazine nitrile cathepsin K inhibitor and its application in the preparation of medicines for treating osteoarthritis
  • Hydrazine nitrile cathepsin K inhibitor and its application in the preparation of medicines for treating osteoarthritis
  • Hydrazine nitrile cathepsin K inhibitor and its application in the preparation of medicines for treating osteoarthritis

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Embodiment Construction

[0074] Under the premise of existing (±)E4(para- / meta-) synthesis [26] , take 0.61g parent compound (±)E4(para-), and other compounds obtained from commercial sources: 0.43g p-(±)methylsulfonyl phenylboronic acid ((4-(methylsulfonyl)phenyl)boronic acid), 65.3 mg[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 ) and 0.5 g of potassium carbonate powder were added into a 100 mL round-bottomed flask with a stirring magnet, then 40 mL of tetrahydrofuran was added into the round-bottomed flask as a reaction solvent, and then 2 mL of water was injected with a pipette. After charging and pumping the reaction system three times (nitrogen-vacuum), heat and reflux for about 6 hours [27] . The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the tetrahydrofuran in the flask was evaporated to dryness with a rotary evaporator. Then add 60 mL of ethyl acetate and 20 mL of water, separate the organic phase with a s...

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Abstract

The invention relates to a hydrazinonitrile cathepsin K inhibitor, and an application thereof in preparation of osteoarthritis treatment drugs, and belongs to the technical field of cathepsin inhibitors. The inhibitor contains a novel P3 group with different orientations, has a nano-mole concentration level inhibition effect on cathepsin K outside cells, has hundreds-of-times or above selectivity to cathepsin K, cathepsin S and cathepsin B, and also has hundreds-of-times or above selectivity to highly homologous cathepsin K and cathepsin L. Culture is carried out under the following two conditions: (1) cell passage and (2) ascorbic acid and beta-glycerophosphoric acid stimulation with primary chondrocytes as a model. Results of gelatin zymography and quantitative fluorescence assay tests show that the expression level of the cathepsin K under every one of the above two conditions is increased; and the activity of the cathepsin K is reduced after the novel inhibitor is added. The inhibitor also has a good inhibition effect in the cells, and has a very good inhibition effect on the cathepsin K.

Description

technical field [0001] The invention belongs to the technical field of cathepsin inhibitors, and in particular relates to a novel and highly efficient hydrazinonitrile-type cathepsin inhibitor, which greatly improves the selectivity of cathepsin K, B, L, and S, and is used in the preparation and treatment of osteoarthritis It has potential application in the related drugs of osteoarthritis, so it has important clinical significance for the treatment of osteoarthritis and related diseases. Background technique [0002] Osteoarthritis (OA) is a series of diseases caused by the interaction of mechanical injury and biological factors. As a degenerative joint disorder, osteoarthritis is mainly characterized by destruction of articular cartilage, changes in subchondral bone, and synovitis, which seriously affects the daily life of patients. [1] ;In the next few years, bone and joint diseases will attract more and more attention [2] . The pathogenesis of OA is very complex, and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C317/44A61K31/277A61P19/02A61P29/00
CPCC07C317/44
Inventor 吴玉清原晓喻瑞内·布希萨伊达·梅霸瑞克
Owner JILIN UNIV
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