Application of compound Nxa in preparation of medicine for treating Alzheimer disease and medicine composition of compound Nxa

Abstract

The invention relates to the technical field of new pharmacological action of a compound Nxa, and particularly discloses application of the compound Nxa in preparation of a medicine for treating Alzheimer's disease and a medicine composition of the compound Nxa. The chemical name of the compound Nxa is 2, 3, 4, 4 '-tetrahydroxybenzophenone-1, 2-diazido naphthoquinone-5-sulfonate, the molecular formula of the compound Nxa is C22H18O11, the new application of the compound Nxa in treatment of the Alzheimer's disease fills the blank in the field of micromolecule GLP-1 RA special for treating AD, and a new drug choice is provided for treatment and alleviation of the Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of new pharmacological effects of compound Nexa, and in particular to a new application of a compound in a medicament for treating Alzheimer's disease, and a pharmaceutical composition for treating Alzheimer's disease comprising the compound. BACKGROUND

[0002] Alzheimer's disease (hereinafter referred to as AD) is a neurodegenerative disease with insidious onset and progressive development. It is the most common type of dementia, accounting for about 60-80% of all cases. The main clinical manifestations of AD are memory impairment, agnosia, apraxia, aphasia, and executive function decline, which seriously affect the daily life and social function of patients.

[0003] The exact cause of AD has not been fully elucidated, and it is currently believed to be the result of the combined effects of genetics, environment, and lifestyle. In recent years, the relationship between glucagon-like peptide-1 (GLP-1) and Alzheimer's disease has become a popular direction in the field of neuroscience and drug development. Research has shown that GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide and liraglutide, can have potential therapeutic and preventive effects on Alzheimer's disease through various indirect and direct mechanisms. Preclinical experimental studies have shown that GLP-1 RAs have significant effects on AD transgenic mouse models, improving memory, reducing Aβ plaques and Tau tangles, and other effects. Epidemiological studies have also found that patients taking GLP-1 RAs for diabetes treatment have a significantly lower risk of developing dementia than those taking other hypoglycemic drugs.

[0004] However, except for a few small molecules such as PF-06882961 (whose indications are mainly for diabetes or obesity, not specifically for AD), there is currently a lack of an approved or late-stage clinical oral small molecule GLP-1 RA specifically for AD on the market, i.e., there is still a significant practical gap in this field. SUMMARY

[0005] One of the purposes of the present application is to provide a new application of compound Nexa in the field of Alzheimer's disease treatment, to fill the gap in the field of small molecule GLP-1 RAs specifically for treating AD.

[0006] The second purpose of the present application is to provide a pharmaceutical composition comprising compound Nexa, so that the pharmaceutical composition has the efficacy of treating Alzheimer's disease.

[0007] The application is realized by the following technical solutions:

[0008] In a first aspect, the application relates to the use of a compound Nexa in the preparation of a medicament for treating Alzheimer's disease, wherein the compound Nexa has a chemical name of 2,3,4,4'-tetrahydroxybenzophenone-1,2-diazido naphthoquinone-5-sulfonate, a molecular formula of C 22 H 18 O 11 , and a structure as shown in the following: .

[0009] In the research, the inventors found that the compound Nexa has a high affinity interaction with the target GLP-1. After grouping and dosing experiments on APP / PS1 transgenic AD mice, and through water maze and Y maze experiments, it can be confirmed that after taking the compound Nexa, the working memory, spatial cognition and exploration behavior of the APP / PS1 transgenic AD mice are significantly improved. At the same time, after the GLP-1R is blocked, the above-mentioned improvement disappears. Finally, after the APP / PS1 transgenic AD mice completing the relevant biological experiments are sacrificed and pathological Nissl staining is observed, it is found that the compound Nexa can effectively reduce the pathological damage of hippocampal neurons of the APP / PS1 transgenic AD mice, and the protection effect disappears in the mice with blocked GLP-1 receptor, further confirming that the compound Nexa can achieve the function of nerve repair and depends on the activation of the GLP-1R pathway.

[0010] As a further improvement of the application, the administration mode of the medicament for treating Alzheimer's disease includes at least one of intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual administration, intralesional or intracerebral delivery, and spray administration.

[0011] As a further improvement of the application, the administration mode of the medicament for treating Alzheimer's disease includes at least one of oral administration, intramuscular injection, subcutaneous injection or intravenous injection.

[0012] As a further improvement of the application, the medicament for treating Alzheimer's disease includes a preparation of the compound Nexa and a pharmaceutically acceptable carrier, and the preparation dosage form is selected from one of injection, capsule, tablet, granule, suspension, emulsion, spray, powder, liposome, oral liquid and dripping pill.

[0013] As a further improvement of the application, the preparation dosage form is injection.

[0014] As a further improvement of the application, the compound Nexa is a pharmaceutically acceptable salt thereof.

[0015] As a further improvement of the present application, the salt is selected from any one or more of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinate, tartarate, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxybenzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, mesitylenesulfonate, hydroquinonesulfonate and p-toluenesulfonate.

[0016] As a further improvement of the present application, the Alzheimer's disease comprises any one or more of memory impairment, impaired cognitive function, loss of neurons in the hippocampus of the brain, apoptosis.

[0017] As a further improvement of the present application, the compound Nexa achieves the function of nerve repair through activation of the GLP-1 R pathway.

[0018] In a second aspect, the present application provides a pharmaceutical composition comprising the compound Nexa as described in any one of the above items for treating the Alzheimer's disease.

[0019] The present application has the beneficial effect that the present application discloses a new application of the compound Nexa in the treatment of Alzheimer's disease, fills the gap in the field of small molecule GLP-1 RAs dedicated to the treatment of AD, and provides a new drug selection for the treatment and alleviation of Alzheimer's disease; and the pharmaceutical composition provided by the present application has various administration modes, including intramuscular injection, subcutaneous injection, intravenous injection, oral administration and other modes, which is convenient for clinical application; accordingly, the pharmaceutical composition provided by the present application can also be made into various dosage forms, such as injection, capsule and tablet, which can meet the medication needs of different patients. BRIEF DESCRIPTION OF DRAWINGS

[0020] The following drawings are provided to assist in the understanding of the objects and advantages of the present application in combination with preferred embodiments of the present application, wherein:

[0021] Figure 1 is a structural diagram of the compound Nexa;

[0022] Figure 2 is a summary diagram of the binding ability detection results of the compound Nexa and the target human GLP-1 R;

[0023] Figure 3 is a summary diagram of the mouse water maze test results;

[0024] Figure 4 is a summary diagram of the mouse Y maze test results;

[0025] Figure 5 is a summary diagram of the hippocampal Nissl staining results of the mice in each group.

[0026] InFigure 3 In the figure, A is the swimming speed, B is the platform quadrant residence time, C is the distance ratio of the mouse in the platform quadrant, D is the number of times the mouse enters the platform, E is the escape latency of the mouse, F is the change of the escape latency of the mouse, and G is the typical swimming route of the mouse.

[0027] In the figure, A is the swimming speed, B is the platform quadrant residence time, C is the distance ratio of the mouse in the platform quadrant, D is the number of times the mouse enters the platform, E is the escape latency of the mouse, F is the change of the escape latency of the mouse, and G is the typical swimming route of the mouse. Figure 4 In the figure, A is the total number of times the mouse enters the arm within 8 minutes, B is the spontaneous alternation rate of the mouse, C is the number of times the mouse enters the new arm, and D is the exploration duration of the mouse in the new arm. DETAILED DESCRIPTION

[0028] The application will be further described in detail below according to the accompanying drawings and examples.

[0029] In order to make the purpose, technical solutions and advantages of the application clearer, further detailed description of the application will be given in combination with the accompanying drawings and examples. It should be understood that the specific examples described herein are only used to explain the application, rather than all examples. Based on the examples in the application, all other examples obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the application.

[0030] Example 1

[0031] This example is used to test the binding ability of compound Nexa to the target human GLP-1R. In this example, the binding ability is quantitatively analyzed by surface plasmon resonance technology (hereinafter referred to as SPR). In the SPR experiment for detecting small molecule-protein interaction, the protein is fixed on the surface of the biosensor, and the small molecule flows through the surface of the sensor chip; during the interaction between the small molecule and the protein, the subsequent change in refractive index will be reflected, and after monitoring the refractive index, the resonance unit is used to quantify the monitoring results.

[0032] The monitoring results are finally shown in Figure 2 As can be seen from the SPR sensorgram, compound Nexa can bind to human GLP-1R protein in a concentration-dependent manner, and through kinetic fitting, the equilibrium dissociation constant (KD) value of Nexa and human GLP-1R can be measured as 246 uM, which indicates that there is a high-affinity interaction between them. This example proves the authenticity and correctness of the underlying mechanism in the application of compound Nexa in the treatment and alleviation of Alzheimer's disease.

[0033] Example 2

[0034] The therapeutic effect of compound Nexa is tested in this embodiment. The test process mainly includes mouse water maze test, mouse Y maze test and observation of mouse Mani's staining. The specific detection steps mainly include the following:

[0035] (1) Preparation of Alzheimer's disease mouse model and grouping of administration method

[0036] In this embodiment, 6-month-old APP / PS1 double transgenic mice are selected as disease models, and C57BL / 6 wild type mice of the same age are used as normal control group.

[0037] The mice are randomly divided into 6 groups, and the composition of each group is mainly as follows:

[0038] ① Composition includes C57BL / 6 wild type mice. In this group, physiological saline is injected into the mouse body, so it is called WT+saline group;

[0039] ② Composition includes APP / PS1 double transgenic mice. In this group, physiological saline is injected into the mouse body, so it is called APP / PS1+saline group;

[0040] ③ Composition includes APP / PS1 double transgenic mice. In this group, liraglutide is injected into the mouse body, that is, a GLP-1 RAs is injected, so it is called APP / PS1+Liraglutide group;

[0041] ④ Composition includes APP / PS1 double transgenic mice. In this group, a GLP-1 receptor blocker Exendin-9-39 is first injected into the mouse body, and then a small amount (2 mg / kg) of compound Nexa is injected, so it is called APP / PS1+Exendin9-39+Nexa (2 mg / kg) group;

[0042] ⑤ Composition includes APP / PS1 double transgenic mice. In this group, a small amount (2 mg / kg) of compound Nexa is injected into the mouse body, so it is called APP / PS1+Nexa (2 mg / kg) group;

[0043] ⑥ Composition includes APP / PS1 double transgenic mice. In this group, a large amount (5 mg / kg) of compound Nexa is injected into the mouse body, so it is called APP / PS1+Nexa (5 mg / kg) group.

[0044] Each group contains 8 mice, and each mouse is injected intraperitoneally. Behavioral tests are performed after 4 weeks of administration, and administration is continued during the test period.

[0045] (2) Mouse water maze test

[0046] In this embodiment, the Morris water maze test system was used to evaluate the spatial cognitive function of each group of mice, focusing on the analysis of swimming speed, target quadrant residence time, movement distance ratio, platform crossing frequency, escape latency and other indicators, and the change trend of the escape latency of mice on the 1st to 5th day was recorded.

[0047] The overall test results are shown in Figure 3 , and the swimming speed of the six groups of experimental mice showed no statistical difference (as shown in Figure 3 A), which indicated that the basic motor function of the APP / PS1 transgenic mice was equivalent to that of the C57BL / 6 wild-type mice (control group), and the drug treatment did not significantly affect their motor ability.

[0048] After 4 weeks of drug treatment, the residence time, movement distance ratio and crossing frequency of the mice in the target platform area in the ③ group and the ⑤-⑥ groups were significantly increased compared with the ② group and the ④ group, and the difference was statistically significant (as shown in Figure 3 B-D), and in addition, there was no significant difference in the above indicators between the ③ group and the ⑤-⑥ groups, which indicated that the compound Nexa was equivalent to the positive drug in improving cognitive function. Among them, the performance of the ④ group mice was significantly worse than that of the other drug groups, indicating that after the GLP-1R was blocked, the compound Nexa failed to effectively improve cognitive function, thereby confirming that the pharmacodynamic effect of the compound Nexa depends on the GLP-1R pathway, and the mechanism relied on by the present application is correct. Figure 3 As shown in F, the ability of each group of mice to learn to find the platform, during the 5-day test process, the escape latency of all groups of mice showed a trend of gradually shortening, but the escape latency of the ② group was significantly higher than that of the ① group. However, after the intervention treatment of the compound Nexa, the escape latency of the APP / PS1 double transgenic mice was significantly shortened, which indicated that the compound had a potential effect on improving spatial learning function; at the same time, as shown in Figure 3 G, the representative swimming path diagram of each group of mice, these intuitive trajectory diagrams further confirmed the authenticity and reliability of the experimental data.

[0049] (3) Y maze test of mice

[0050] In this embodiment, the Y maze test system was used to evaluate the working memory function, spatial memory and exploration ability of each group of mice.

[0051] The results of each group of mice in the spontaneous alternation experiment are shown in Figure 4 A-B. In the 8-minute free exploration experiment in the Y maze, the total number of times that the six groups of experimental mice entered each arm showed no statistically significant difference (as shown in Figure 4As shown in Figure A), the basic motor abilities of the mice in each group were basically the same, and were not significantly affected by the experimental intervention, meaning that the drug treatment did not significantly affect their motor abilities. Figure 4 As shown in Figure B, the spontaneous alternation rate of mice in group ② was significantly lower than that in group ①, indicating a significant deficiency in their working memory. There was no significant difference between mice in group ④ and group M②, further demonstrating that compound Nexa failed to improve working memory impairment after GLP-1R blockade. Furthermore, after 4 weeks of treatment with compound Nexa, the spontaneous alternation rate of mice in groups ⑤ and ⑥ significantly increased, with no significant difference from group ①. This improvement was not observed in group ④, thus proving that compound Nexa effectively improves working memory function in APP / PS1 transgenic mice through a GLP-1R-dependent mechanism.

[0052] The results of the novel heteroarm exploration experiment in each group of mice are as follows: Figure 4 As shown in Figures C-D, compared to group ①, group ② mice exhibited significantly reduced frequency and duration of entry into the novel arm, further confirming impaired spatial memory and exploration abilities. Group ④ showed a slight improvement compared to group ②, but the difference was not statistically significant. However, under the drug administration conditions of groups ⑤-⑥, after intervention with compound Nexa, the number of times mice entered the novel arm and the duration of entry significantly increased, with behavioral performance approaching that of group ①. These results further indicate that compound Nexa can enhance the exploration behavior of APP / PS1 transgenic mice in novel environments and restore their spatial memory abilities via the GLP-1R pathway.

[0053] The results of the Y-maze test show that the compound Nexa significantly improved working memory, spatial cognition, and exploratory behavior in APP / PS1 transgenic mice. Moreover, this effect disappeared after GLP-1R was blocked, further proving that its efficacy depends on GLP-1R activation.

[0054] (4) Pathological Nissl staining observation experiment

[0055] Nissl staining is a classic technique in neuropathological analysis. This technique utilizes the specific binding reaction of a basic dye with Nissl bodies, causing Nissl bodies in the neuronal cytoplasm to appear deep blue or purplish-blue, while the cell nucleus and other background tissues stain lighter. This allows for a direct visualization of the abundance, distribution, and overall morphology of Nissl bodies within neurons. This technique is commonly used to assess the synthetic activity and structural integrity of neurons and is an important basis for determining whether neurons exhibit pathological changes such as damage, degeneration, fatigue, or apoptosis.

[0056] The results of Nissl staining of the hippocampus in each group of mice are as follows: Figure 5As shown in the figure, in group ①, the neurons in the hippocampal DG, CA3, and CA1 regions of mice were morphologically regular and densely arranged, with abundant and uniformly stained Nissl bodies in the cytoplasm. In contrast, the number of neurons in the CA1 region of the hippocampus of mice in group ② was significantly reduced, the arrangement was loose, and there were severe pathological changes such as nuclear dissolution, loss of Nissl bodies, and lighter staining. Mice in groups ③ and ⑤-⑥ all showed significant neuroprotective effects, characterized by more regular neuronal arrangement, a significant recovery in the number of Nissl bodies, and effective inhibition of cell atrophy and vacuolation. However, mice in group ④ did not show similar improvement; the neuronal pathological morphology was only slightly improved compared to group ②, and the Nissl body content did not recover significantly.

[0057] The above results indicate that the compound Nexa can effectively alleviate the pathological damage to hippocampal neurons in APP / PS1 transgenic mice, and this protective effect disappears after the GLP-1 receptor is blocked. Furthermore, it is confirmed that the neural repair function of Nexa depends on the activation of the GLP-1R pathway.

[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. The application of compound Nexa in the preparation of drugs for treating Alzheimer's disease, characterized in that: The chemical name of the compound Nexa is 2,3,4,4'-tetrahydroxybenzophenone-1,2-diazidonaphthoquinone-5-sulfonate, and its molecular formula is C2. 22 H 18 O 11 It has the following structure: 。 2. The application according to claim 1, characterized in that, Drugs for treating Alzheimer's disease can be administered via at least one of the following methods: intramuscular injection, subcutaneous injection, intravenous injection, oral administration, sublingual administration, delivery to the lesion or brain, or aerosol administration.

3. The application according to claim 2, characterized in that, Drugs for treating Alzheimer's disease can be administered orally, intramuscularly, subcutaneously, or intravenously, at least one of these methods.

4. The application according to claim 1, characterized in that, The medicine for treating Alzheimer's disease includes a formulation made of the compound Nexa with a pharmaceutically acceptable carrier, the dosage form of which is selected from one of the following: injection, capsule, tablet, granule, suspension, emulsion, spray, powder, liposome, oral liquid, and pellet.

5. The application according to claim 4, characterized in that, The dosage form is an injection.

6. The application according to claim 1, characterized in that, The compound Nexa is a pharmaceutically acceptable salt of itself.

7. The application according to claim 6, characterized in that, The salt is selected from any one or more of acetate, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, benzoate, fumarate, maleate, succinic acid, tartaric acid, citrate, oxalic acid, glyoxylic acid, aspartic acid, tartrate, 2,5-dihydroxybenzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, lecithin sulfonate, hydroquinone sulfonate, and p-toluenesulfonate.

8. The application according to claim 1, characterized in that, The Alzheimer's disease includes any one or more of the following: memory impairment, cognitive dysfunction, loss or apoptosis of neurons in the hippocampus of the brain.

9. The application according to claim 1, characterized in that, The compound Nexa achieves its neural repair function by activating the GLP-1R pathway.

10. A pharmaceutical composition, characterized in that, The compound Nexa, comprising any one of claims 1 to 9, is used to treat the Alzheimer's disease.

Images