阅读说明：本技术 双吲哚马来酰亚胺类pkc抑制剂在制备治疗心肌炎心律失常药物中的应用 (Application of bisindolylmaleimide PKC inhibitor in preparation of medicine for treating myocarditis arrhythmia ) 是由 钟春莲 赵欢 戚智 卢余盛 贾力 于 2020-05-25 设计创作，主要内容包括：本发明属医药领域,公开了双吲哚马来酰亚胺类PKC抑制剂在制备预防或治疗心肌炎心律失常药物中的应用。本发明所述的双吲哚马来酰亚胺类PKC抑制剂具有高效低毒性,其作用机制为通过抑制心电图QRS波群的延长达到抗心律失常的作用。其在离体心脏中,显示了良好的抑制QRS波群延长的药物活性；动物实验显示,其对心肌炎心律失常具有显著的治疗效果。本发明首次提出PKC抑制剂可用于安全有效地治疗心肌炎心律失常,可开发为治疗QRS波群延长型心律失常的临床药物。(The invention belongs to the field of medicines, and discloses application of a bisindolylmaleimide PKC inhibitor in preparation of a medicine for preventing or treating myocarditis arrhythmia. The bisindolylmaleimide PKC inhibitor has high efficiency and low toxicity, and the action mechanism of the inhibitor is that the inhibitor achieves the effect of resisting arrhythmia by inhibiting the prolongation of QRS complex of electrocardiogram. It shows good pharmaceutical activity for inhibiting QRS complex prolongation in isolated heart; animal experiments show that the traditional Chinese medicine composition has a remarkable treatment effect on myocarditis arrhythmia. The invention provides a PKC inhibitor for the first time, which can be used for safely and effectively treating myocarditis arrhythmia and can be developed into a clinical medicament for treating QRS complex-prolonged arrhythmia.)

1. The application of the bisindolylmaleimide PKC inhibitor in preparing the medicine for treating myocarditis arrhythmia is characterized in that: the chemical name of the bisindolylmaleimide is

3-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione，

The molecular formula is C28H28N4O2,

the chemical structure is as follows:

the bisindolylmaleimide PKC inhibitor is applied to preparation of medicines for treating myocarditis arrhythmia.

2. The use of a bisindolylmaleimide PKC inhibitor according to claim 1 in the preparation of a medicament for the treatment of myocarditis arrhythmia, characterized in that: the application of the bisindolylmaleimide PKC inhibitor in preparing medicines for inhibiting prolongation of QRS wave complex of electrocardiogram.

3. The use of a bisindolylmaleimide PKC inhibitor according to claim 1 in the preparation of a medicament for the treatment of myocarditis arrhythmia, characterized in that: use of said bisindolylmaleimides for the preparation of a medicament for the prolongation of the QRS complex and arrhythmia caused by PKC activation.

4. The use of a bisindolylmaleimide PKC inhibitor according to claim 1 in the preparation of a medicament for the treatment of myocarditis arrhythmia, characterized in that: the bisindolylmaleimide is used for preparing the medicine for inhibiting the abnormal shape and distribution of the gap junction protein 43.

5. The use of a bis-indole maleimide PKC inhibitor according to claim 4 in the manufacture of a medicament for the treatment of myocarditis arrhythmia, wherein: the bisindolylmaleimide is applied to preparing the medicine for inhibiting the function abnormity of the gap junction channel of the gap junction protein 43.

6. The use of a bisindolylmaleimide PKC inhibitor according to claims 1-5 in the manufacture of a medicament for the treatment of myocarditis arrhythmia, characterized in that: the medicine forms are tablets, capsules, liposomes, granules, injections and oral agents, namely other pharmaceutically acceptable various medicine forms.

Technical Field

The invention belongs to the technical field of application of bisindolylmaleimide PKC inhibitors, and particularly relates to application of a bisindolylmaleimide PKC inhibitor in preparation of a medicine for treating myocarditis arrhythmia.

Background

Arrhythmia is the external manifestation of abnormal conduction of electrical signals in myocardial cells, and malignant arrhythmia can induce acute sudden cardiac death of a patient and seriously harm the physical health of the patient. In recent years, with the change of life style and the increase of working pressure, the sudden death rate of young and middle-aged people is increased year by year, pathological biopsy shows that 2-42% of patients die from myocarditis-induced sudden cardiac death, and myocardial inflammatory arrhythmia has become a main factor of sudden death of the patients. However, the current treatment of myocarditis mainly aims at improving symptoms, no effective treatment medicine exists, and how to prevent arrhythmia-induced sudden cardiac death in time becomes a key problem to be solved urgently for myocarditis treatment.

Abnormal QRS complexes significantly increase the risk of ventricular arrhythmias and sudden cardiac death. The QRS complex is the widest complex in the electrocardiogram, reflecting the conduction of electrical signals in the ventricular musculature, while the prolonged QRS complex (≧ 120ms) reflects the asynchrony of the electrical signals in the ventricle. Therefore, prolongation of the QRS complex and changes in morphology can predict the current state of the heart and the condition of arrhythmia. Numerous studies have demonstrated that prolonged QRS complexes are closely associated with cardiomyopathy, left ventricular dysfunction, poor prognosis, and higher mortality. In patients with ventricular tachycardia, the QRS complex is significantly prolonged in about 72% of patients. Every 1ms of extension of the QRS complex, the patient's risk of developing persistent ventricular tachycardia increases by 2.4%; every 10ms of prolongation of the QRS complex, the mortality rate of patients with ventricular arrhythmias increases by 10%. Moreover, patients with prolonged QRS complexes have poorer prognosis and a higher risk of relapse into ventricular arrhythmias. In patients with heart failure, mortality rates for patients with prolonged QRS complex and normal QRS complex are 51% and 34%, respectively. The prolonged QRS complex has become an indicator of predicting overall mortality in patients with ischemic cardiomyopathy, myocardial infarction, and arrhythmia. In addition, studies have shown that prolonged QRS complexes are closely associated with sudden cardiac death. In patients with sudden coronary death, the QRS complex is significantly prolonged, which has become an independent predictor of sudden death in patients with coronary heart disease. The phenomenon of severe QRS complex prolongation exists in patients with myocarditis and animal models, and the prolonged QRS complex obviously increases the risk of sudden death of patients with myocarditis.

Disclosure of Invention

The invention aims to provide a bisindole maleimide PKC inhibitor which is applied to the preparation of medicines for treating myocarditis arrhythmia, recovers the function of a Cx43 gap connecting channel between myocardial cells, essentially relieves the prolongation of QRS wave group and achieves the effect of resisting arrhythmia.

The invention specifically comprises the following contents:

bisindolylmaleinamide PKC inhibitors are known to inhibit T cell activation, anti-inflammatory, anti-tumor, and alleviate heart failure. The invention provides application of the compound in preparing anti-myocarditis arrhythmia medicines. The invention verifies the effect of the bisindolylmaleimide PKC inhibitor in myocarditis arrhythmia by constructing a myocarditis animal model, and verifies that the bisindolylmaleimide PKC inhibitor can be used as a medicine for safely and effectively treating myocarditis arrhythmia.

The chemical name of the bisindolylmaleimide PKC inhibitor is as follows:

3-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione，

the molecular formula is C28H28N4O2,

the chemical structure is as follows:

further, the application of the bisindolylmaleimide PKC inhibitor in preparing a medicament for inhibiting prolongation of QRS wave group of electrocardiogram.

And the use of said bisindolylmaleimide PKC inhibitors for the preparation of a medicament for the prolongation of the QRS complex and arrhythmia resulting from PKC activation.

Applicants found that PKC activation significantly promoted prolongation of the QRS complex of electrocardiograms, inducing arrhythmia (FIG. 2). And the PKC is firstly verified to be activated in an isolated heart rat to obviously cause the prolongation of the QRS wave complex of the electrocardiogram, and further proves the effect of the PKC in arrhythmia. The invention proves that activating PKC can cause the prolongation of the QRS wave complex of electrocardiogram, thereby causing arrhythmia, and provides powerful experimental evidence for the PKC inhibitor as a potential drug capable of inhibiting myocarditis arrhythmia.

Further, the application of the bisindolylmaleimide PKC inhibitor in preparing a medicament for inhibiting the abnormal shape and distribution of gap junction protein 43 is provided.

And the application of the bisindolylmaleimide PKC inhibitor in preparing a medicament for inhibiting the dysfunction of the gap junction channel of the gap junction protein 43.

The formation of electrical activity in the heart depends primarily on various ion channels, regulatory proteins and interstitial connecting channels between the cardiac muscle cells. Therefore, the invention detects the effect of the bisindolylmaleimide PKC inhibitor on the myocardial intercellular gap junction protein Cx 43. The experimental results show that: the morphology of myocardial tissue Cx43 of rats in the EAM group is changed from a normal compact state to a dispersed state, and the distribution is transferred from the intercalated disc to the two sides of the cells; while the morphology and distribution of myocardial tissue Cx43 in the treated rats gradually returned to normal (FIG. 3). The results show that the bisindolylmaleimide PKC inhibitor can improve the function of a Cx43 gap connecting channel caused by myocarditis, thereby relieving the prolongation of QRS wave complex.

Further, the pharmaceutical forms are tablets, capsules, liposomes, granules, injections and oral preparations, i.e. other pharmaceutically acceptable pharmaceutical forms.

The invention has the advantages and beneficial effects that:

the research result of the applicant indicates that the diindolylmaleimide PKC inhibitor can restore the function of a Cx43 gap junction channel and promote the conduction of an electric signal between cardiac muscle cells through inhibiting the abnormal shape and distribution of gap junction protein Cx43 caused by myocarditis, thereby inhibiting the extension of electrocardiogram QRS wave group and playing a role in resisting arrhythmia. In addition, the applicant further proves that the PKC has the effect of promoting arrhythmia through research on PKC and arrhythmia, and conversely proves that the PKC inhibitor has the effect of resisting arrhythmia.

The current antiarrhythmic drugs used clinically mainly comprise blockers of various ion channels. The bisindolylmaleimide PKC inhibitor has the main functions as follows: the function of a Cx43 gap connecting channel is restored to relieve the prolongation of QRS wave group, and the effect of resisting arrhythmia is achieved. The compound can essentially inhibit arrhythmia, has different surface effects from the prior blocking ion channels, and is expected to realize the search of antiarrhythmic drugs from new visual fields.

Drawings

FIG. 1 is a graph showing the results of experiments on the inhibition of EAM rat QRS complex elongation by bis-indole maleimide PKC inhibitors.

Figure 2 is a graph of the effect of PKC activation on the QRS complex of the isolated heart of normal rats.

FIG. 3 is a schematic diagram showing the inhibitory effect of a PKC inhibitor of bisindole maleimide on abnormal morphology and distribution of CX43 in EAM rats.

Detailed Description

The bisindolylmaleimide PKC inhibitor disclosed by the invention has known effects of inhibiting T cell activation, resisting inflammation, resisting tumor, relieving heart failure and the like. The invention provides a new application of the compound in myocarditis arrhythmia, the compound is used as a PKC inhibitor to prepare a medicine for treating myocarditis arrhythmia, and can inhibit the prolongation of QRS wave group of electrocardiogram and inhibit the abnormal form and distribution of gap junction protein 43. The following examples are intended to illustrate the invention without limiting its scope.