阅读说明：本技术 异吲哚酮类化合物在制备防治溶骨性疾病药物中的应用 (Application of isoindolone compound in preparation of medicine for preventing and treating osteolytic diseases ) 是由 顾琼 佘志刚 华沛 崔辉 蔡润林 于 2019-09-19 设计创作，主要内容包括：本发明公开了异吲哚酮类化合物在制备防治溶骨性疾病药物中的应用。该异吲哚酮类化合物具有式(I)所示结构：<Image he="548" wi="700" file="DDA0002207783820000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>该异吲哚酮类化合物可显著性抑制RANKL诱导的骨髓源巨噬细胞BMMs向破骨细胞分化的能力和破骨细胞的骨吸收能力,且呈浓度依赖性；后续机制研究发现,异吲哚酮类化合物通过阻碍RANKL诱导的MAPK和PI3K/AKT信号转导通路的激活来抑制转录因子NFATc1的表达,从而下调破骨细胞相关基因的表达,发挥抑制破骨细胞分化和骨吸收的能力。此外,异吲哚酮类化合物不影响成骨细胞的分化,揭示了异吲哚酮类化合物在防治溶骨性疾病中的应用,可以与常规药用载体制成的药物组合物,对溶骨性疾病进行防治。(The invention discloses application of isoindolinone compounds in preparation of a medicament for preventing and treating osteolytic diseases. The isoindolone compound has a structure shown in a formula (I): the isoindolone compound can remarkably inhibit the differentiation capability of bone marrow-derived macrophage BMMs induced by RANKL to osteoclasts and the bone absorption capability of the osteoclasts, and is concentration-dependent; subsequent mechanism researches find that the isoindolone compound inhibits the expression of transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, so that osteoclast is down-regulatedThe expression of the cell-associated gene exerts the ability to inhibit osteoclast differentiation and bone resorption. In addition, the isoindolone compound does not influence the differentiation of osteoblasts, discloses the application of the isoindolone compound in preventing and treating osteolytic diseases, and can be used for preventing and treating osteolytic diseases together with a pharmaceutical composition prepared from a conventional medicinal carrier.)

1. Application of isoindolone compound with structure shown in formula (I) in preparation of medicine for preventing and treating osteolytic diseases

2. The use according to claim 1, wherein the osteolytic disease is a bone disease resulting from an increased number and/or activity of osteoclasts.

3. The use of claim 2, wherein the osteolytic disease is one or more of bone destruction, inflammatory osteolysis, aseptic loosening of prosthesis after artificial joint replacement, postmenopausal osteoporosis, Page's disease, psoriatic arthritis, or ankylosing spondylitis.

4. The use according to claim 1, characterized in that the isoindolones are used for inhibiting the expression of the transcription factor NFATc 1.

5. The use according to claim 4, characterized in that the isoindolones are used for inhibiting RANKL-induced activation of the MAPK and PI3K/AKT signaling pathways.

Technical Field

The invention relates to the technical field of compounds and medicines, in particular to application of isoindolinone compounds in preparation of medicines for preventing and treating osteolytic diseases.

Background

Osteolytic disease (osteolytic disease) is a systemic bone disease in which bone fragility is increased due to decreased bone density and bone quality and destruction of bone microarchitecture resulting from increased osteoclast number and increased activity, and thus fracture is likely to occur. A large body of literature currently shows that RANKL-mediated osteoclast recruitment is intimately involved in various types of pathological osteolysis, for example: tumor-induced bone destruction, inflammatory osteolysis, aseptic prosthesis loosening after artificial joint replacement, postmenopausal osteoporosis, Page's disease, psoriatic arthritis, ankylosing spondylitis, and the like. With the advent of the global aging society, bone destruction caused by various osteolytic diseases has become a serious challenge for medical workers. In recent years, the drug therapy of osteolytic diseases mainly comprises drugs for inhibiting bone resorption, drugs for promoting bone formation and basic supplements, but the first-line drug bisphosphonate drugs for inhibiting bone resorption excessively promote bone mineralization and also cause the increase of bone fragility after long-term application; the bone formation promoting medicine is also often accompanied with adverse reactions such as palpitation and canceration. Therefore, the search for a safe and effective drug for treating osteolytic diseases is still a difficult problem for medical workers. Natural products are important sources for drug development and have been a few successful precedent, and natural compounds with osteoclast inhibitory activity have been reported, including lignin, diterpenes, sesquiterpene lactones, and the like.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides application of isoindolone compounds in preparation of medicines for preventing and treating osteolytic diseases. The research of the inventor discovers that the isoindolone compound with a specific structure can remarkably inhibit the differentiation capability of bone marrow-derived macrophage BMMs to osteoclasts induced by RANKL and the bone absorption capability of the osteoclasts, and is concentration-dependent; subsequent mechanism researches find that the isoindolone compound inhibits the expression of a transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, so that the expression of osteoclast-related genes is reduced, and the capability of inhibiting osteoclast differentiation and bone resorption is exerted. In addition, the isoindolone compound does not influence the differentiation of osteoblasts, discloses the application of the isoindolone compound in preventing and treating osteolytic diseases, and can be prepared into a pharmaceutical composition with a conventional medicinal carrier to prevent and treat osteolytic diseases such as osteoporosis, peyer's disease and the like. The invention provides a new medicine for osteolytic diseases and has larger clinical application value.

In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:

the application of the isoindolone compound with the structure shown in the formula (I) in preparing the medicament for preventing and treating the osteolytic disease is as follows:

the inventor of the invention obtains a series of isoindolone compounds by separating the isoindolone compounds from fermentation liquor of marine fungus Diaporthe sp. In order to better develop and utilize the series of isoindolinone compounds, the isoindolinone compounds are researched more widely and intensively.

The research finds that the isoindolone compound with the specific formula structure of the formula (I) in the series of isoindolone compounds can remarkably inhibit the differentiation capability of bone marrow-derived macrophage BMMs to osteoclasts induced by RANKL and the bone resorption capability of the osteoclasts and is in concentration dependence; subsequent mechanism researches find that the isoindolone compound inhibits the expression of a transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, so that the expression of osteoclast-related genes is reduced, and the capability of inhibiting osteoclast differentiation and bone resorption is exerted. In addition, the isoindolone compound does not influence the differentiation of osteoblasts, discloses the application of the isoindolone compound in preventing and treating osteolytic diseases, and can be prepared into a pharmaceutical composition with a conventional medicinal carrier to prevent and treat osteolytic diseases such as osteoporosis, peyer's disease and the like.

The invention provides a new medicine for osteolytic diseases and has larger clinical application value.

The isoindolone compound can be prepared by the patent CN 107721990A.

The pharmaceutical composition prepared from the isoindolone compound as an active ingredient and a conventional pharmaceutical carrier can prevent and treat osteolytic diseases. Specifically, the pharmaceutical composition can be in the form of tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained release tablets, capsules, soft capsules, dripping pills, granules, injections, powder injections or aerosols and the like.

Preferably, the osteolytic disease is a bone disease resulting from an increased number and/or activity of osteoclasts.

More preferably, the osteolytic disease is one or more of bone destruction, inflammatory osteolysis, aseptic prosthesis loosening after artificial joint replacement, postmenopausal osteoporosis, Page's disease, psoriatic arthritis, or ankylosing spondylitis.

Preferably, the isoindolone compound is applied to inhibiting the expression of a transcription factor NFATc 1.

Preferably, the isoindolones are used for inhibiting RANKL-induced activation of MAPK and PI3K/AKT signaling pathways.

Compared with the prior art, the invention has the following advantages and effects:

the isoindolone compound is tested for inhibiting the activity of osteoclast differentiation, and the result shows that the isoindolone compound obviously inhibits the differentiation capability of bone marrow-derived macrophage BMMs induced by RANKL to osteoclasts and the bone resorption capability of the osteoclasts and is concentration-dependent. Subsequent mechanism researches find that the isoindolone compound inhibits the expression of a transcription factor NFATc1 by blocking the activation of MAPK and PI3K/AKT signal transduction pathways induced by RANKL, so that the expression of osteoclast-related genes is reduced, and the capability of inhibiting osteoclast differentiation and bone resorption is exerted. In addition, the isoindolone compound does not influence the differentiation of osteoblasts, discloses the application of the isoindolone compound in preventing and treating osteolytic diseases, and can be prepared into a pharmaceutical composition with a conventional medicinal carrier to prevent and treat osteolytic diseases such as osteoporosis, peyer's disease and the like.

The invention provides a new medicine for osteolytic diseases and has larger clinical application value.

Drawings

FIG. 1 is a graph of isoindolones inhibiting RANKL-induced differentiation of BMMs into osteoclasts;

FIG. 2 shows a diagram of the ability of isoindolones to inhibit bone resorption by osteoclasts;

FIG. 3 is a graph showing the effect of isoindolones on osteoblast differentiation;

FIG. 4 is a graph showing that isoindolones down-regulate RANKL-induced osteoclast-labeling gene expression;

FIG. 5 is a graph showing the activation of the RANKL-induced PI3K/AKT and MAPK pathways by isoindolones.

Detailed Description

The present invention will be further explained with reference to the following examples and drawings, but the examples are not intended to limit the present invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.

Unless otherwise indicated, reagents and materials used in the present invention are commercially available.

The isoindolone compound selected in the embodiments of the invention is prepared by the method in CN 107721990A.