Use of triacetyl-3-hydroxyphenyladenosine in preparation of motion simulation drug

Abstract

Disclosed is the use of triacetyl-3-hydroxyphenyladenosine as shown in formula (I) in the preparation of a motion simulation drug. The triacetyl-3-hydroxyphenyladenosine has a motion simulation effect, and can simulate the motion to significantly improve the blood fat level of obese mice, slow down the weight gain thereof, ameliorate glucose tolerance and liver lipid accumulation, increase oxygen consumption, and reduce the levels of serum inflammatory factors such as TNF-α, IL-1α, IL-1β, IFN-β.

Description

Application of triacetyl-3-hydroxyphenyladenosine in the preparation of motion-mimicking drugs

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 202311522171.6, filed on November 15, 2023, entitled “Application of triacetyl-3-hydroxyphenyladenosine in the preparation of motion simulation drugs,” the entire contents of which are incorporated herein by reference.

[0003] Technology

[0004] The present invention belongs to the field of medical technology, and particularly relates to the use of triacetyl-3-hydroxyphenyladenosine and a pharmaceutical composition containing the same in the preparation of motion simulation drugs. Background Art

[0005] It's widely acknowledged that exercise is beneficial for health. Whether it's metabolic diseases, cancer, or neurological disorders, exercise has demonstrated promising preventive or therapeutic effects. Exercise regulates heart, skeletal muscle, and vascular function, as well as insulin levels, and is considered an important method for preventing and treating cardiovascular disease. Furthermore, exercise can modulate the immune system, inducing the expression of various cytokines, such as interleukin-6, thereby regulating the growth and differentiation of various cells and enhancing the immune system.

[0006] Exercise-mimicking drugs are considered a new class of therapeutics that aim to enhance or simulate the beneficial effects of physical exercise using drugs, replacing real exercise with the overall benefits of exercise. The development of exercise-mimicking drugs has enormous potential for both disease prevention and treatment.

[0007] Triacetyl-3-hydroxyphenyladenosine (also known as IMM-H007 or WS070117, originally published under Patent No. ZL200980101131.6, Publication No. CN101874036B, January 25, 2012) is a novel structural compound identified by the Institute of Materia Medica, Chinese Academy of Medical Sciences, among cordycepin derivatives. It exhibits significant lipid-regulating activity, minimal toxicity, and favorable pharmacokinetics. Currently in clinical development, IMM-H007 has been used in the preparation of motion-mimicking drugs. However, there are no reports on its use in the development of motion-mimicking drugs.

[0008] Summary of the Invention

[0009] The inventors of the present invention have discovered for the first time the exercise-mimicking effect of triacetyl-3-hydroxyphenyladenosine, providing a scientific basis for the clinical application of triacetyl-3-hydroxyphenyladenosine in the development of exercise-mimicking drugs. The structural formula of the triacetyl-3-hydroxyphenyladenosine of the present invention is shown in the following formula (I):

[0010] Therefore, the first aspect of the present application relates to the use of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof as shown in formula (I) in the preparation of an exercise-simulating drug, preferably in the preparation of an exercise-simulating drug for obese subjects.

[0011] The second aspect of the present application relates to the use of a pharmaceutical composition in the preparation of an exercise simulation drug, preferably in the preparation of an exercise simulation drug for obese subjects, wherein the pharmaceutical composition comprises triacetyl-3-hydroxyphenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0012] The third aspect of the present application relates to a method for simulating exercise, which comprises administering triacetyl-3-hydroxyphenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0013] The fourth aspect of the present application relates to a method for simulating exercise, which comprises administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises triacetyl-3-hydroxy-phenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0014] The fifth aspect of the present application relates to the use of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof as shown in formula (I) for simulating exercise or preparing an exercise-simulating drug.

[0015] The sixth aspect of the present application relates to a pharmaceutical composition for simulating exercise or preparing an exercise-simulating drug, the pharmaceutical composition comprising triacetyl-3-hydroxyphenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The seventh aspect of the present application relates to a method for preparing an exercise-simulating drug, the method comprising using triacetyl-3-hydroxyphenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0016] The eighth aspect of the present application relates to a method for preparing a motion simulation drug, which comprises using a pharmaceutical composition comprising triacetyl-3-hydroxy-phenyladenosine represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0017] In the present application, examples of pharmaceutically acceptable salts of the compound of formula (I) include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride (i.e., chloride), bromide, iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate.

[0018] In this application, unless otherwise indicated, when triacetyl-3-hydroxy-phenyladenosine or a pharmaceutically acceptable salt thereof is mentioned by structural formula, name or code, it includes its solvates, hydrates, tautomers, isotope-modified compounds (such as deuterium-modified compounds), and also includes their various solid forms (such as various crystalline forms or amorphous forms).

[0019] In some embodiments, the exercise is moderate-intensity aerobic exercise.

[0020] In some embodiments, the exercise-simulating drug produces an exercise-simulating effect in obese subjects, and the exercise-simulating effect is similar to the health effect produced by exercise; preferably, the exercise-simulating effect is to reduce serum TC, TG, LDL-C and glucose levels, slow weight gain, improve glucose tolerance, liver lipid accumulation, increase oxygen consumption, or reduce serum inflammatory factors TNF-α, IL-1α, IL-1β, IFN-β levels.

[0021] In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, and injections.

[0022] In some embodiments, the pharmaceutical composition is a sustained-release preparation, a controlled-release preparation, or various microparticle delivery systems.

[0023] In some embodiments, the route of administration is selected from oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory tract, dermal, vaginal, and rectal administration.

[0024] In some embodiments, the dosage of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof represented by formula (I) is 0.001-250 mg / kg body weight, preferably 0.1-220 mg / kg body weight, more preferably 100-210 mg / kg body weight, and most preferably 150-200 mg / kg body weight. In some embodiments, the dosage of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof represented by formula (I) is 100 mg / kg body weight, 110 mg / kg body weight, 120 mg / kg body weight, 130 mg / kg body weight, 140 mg / kg body weight, 150 mg / kg body weight, 160 mg / kg body weight, 170 mg / kg body weight, 180 mg / kg body weight, 190 mg / kg body weight, 200 mg / kg body weight, or 210 mg / kg body weight.

[0025] In some embodiments, pharmaceutical compositions or medicaments can be prepared according to methods known in the art. Triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid carriers or excipients and / or other adjuvants to form any dosage form suitable for human or animal use. The content of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof in the pharmaceutical composition or medicament is typically 0.1-99% by weight.

[0026] The triacetyl-3-hydroxy-phenyladenosine or its pharmaceutically acceptable salt or the pharmaceutical composition or drug containing the same of the present invention can be administered in a unit dosage form, and the administration route can be enteral or parenteral administration, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectal administration, etc.

[0027] The dosage form of the triacetyl-3-hydroxy-phenyladenosine or its pharmaceutically acceptable salt or the pharmaceutical composition or drug containing the same of the present invention can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including aqueous injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc. The preferred dosage form of the pharmaceutical composition is selected from tablets, capsules, pills and injections.

[0028] The triacetyl-3-hydroxyphenyladenosine or its pharmaceutically acceptable salt or the pharmaceutical composition or medicine containing the same of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0029] In order to prepare the compound, composition or drug of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants and glidants. The diluent can be selected from one or more of starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate and calcium carbonate; the wetting agent can be selected from one or more of water, ethanol and isopropyl alcohol; the binder can be selected from one or more of starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia glue slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone and polyethylene glycol; the disintegrant can be selected from one or more of dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester and sodium lauryl sulfate; the lubricant and glidant can be selected from one or more of talc, silicon dioxide, stearate, tartaric acid, liquid paraffin and polyethylene glycol.

[0030] Tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0031] To prepare the dosing unit as a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard or soft capsule. Alternatively, the active ingredient compound of the present invention can be mixed with a diluent, a binder, and a disintegrant to form granules or pellets, which can then be placed in a hard or soft capsule. The various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0032] To prepare the compounds or compositions of the present invention as injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators commonly used in the art can be added. Solubilizers or glidants can be selected from one or more of poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters can be selected from one or more of phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators can be selected from one or more of sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol, glucose, and the like can also be added as support agents.

[0033] Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

[0034] To achieve the purpose of medication and enhance the therapeutic effect, the compound, composition or drug of the present invention can be administered by any known administration method.

[0035] The dosage of the compound of the present invention or composition or medicine is according to the character and severity of the disease to be prevented or treated, the individual situation of the patient or animal, and route of administration and dosage form etc. can have wide variations. Generally speaking, the suitable dosage range of the compound of the present invention every day is 0.001-250mg / kg body weight, preferably 0.1-220mg / kg body weight, more preferably 100-210mg / kg body weight, most preferably 150-200mg / kg body weight, such as 100mg / kg body weight, 110mg / kg body weight, 120mg / kg body weight, 130mg / kg body weight, 140mg / kg body weight, 150mg / kg body weight, 160mg / kg body weight, 170mg / kg body weight, 180mg / kg body weight, 190mg / kg body weight, 200mg / kg body weight or 210mg / kg body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and including the dosage regimen utilizing other treatment means.

[0036] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0037] Beneficial technical effects

[0038] The present invention provides a new therapeutic drug for simulating the health effects of exercise - triacetyl-3-hydroxyphenyladenosine, which can simulate the health effects of exercise, has little toxic and side effects, and is safe to use. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below based on specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0040] FIG1 shows the changes in blood lipid and blood glucose levels in mice; FIG1A shows the results after four weeks of drug administration, and FIG1B shows the results after eight weeks of drug administration.

[0041] FIG2 shows Oil Red O staining and HE staining of lipid accumulation in mouse liver; FIG2 shows the results of Oil Red O staining and FIG2 shows the results of HE staining.

[0042] Figure 3 shows the changes in mouse body weight; Graph A shows the changes in mouse body weight, Graph B shows the weight gain of mice, and Graph C shows the average food intake of mice.

[0043] FIG4 shows the changes in glucose tolerance in mice; FIG4 shows the changes in blood glucose levels in mice, and FIG4 shows the AUC of glucose in mice.

[0044] FIG5 shows the changes in oxygen consumption and energy expenditure of mice; FIG5A shows the oxygen intake of mice, FIG5B shows the carbon dioxide emission of mice, and FIG5C shows the energy expenditure of mice.

[0045] Figure 6 shows the levels of serum inflammatory factors in mice; A, B, C and D show the levels of serum inflammatory factors TNF-α, IL-1α, IL-1β and IFN-β, respectively. DETAILED DESCRIPTION

[0046] It should be understood that different applications of the disclosed products and methods can be adjusted according to specific needs in the art. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments of the present invention only and is not intended to be limiting.

[0047] Example

[0048] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention in any way.

[0049] Example 1:

[0050] 1. Experimental Materials

[0051] Roche Active Blood Glucose Meter; Roche Active Test Strips, ROCHE ACCU-CHEK Active; Mouse Serum Inflammatory Factor Detection Kit, LEGENDplex TM Mouse Information Panel (13-plex) 740446; Biosino BG Cholesterol Assay Kit (CHDD-PAP Method); Biosino BG Triglyceride Assay Kit (GPO-PAP Method); Biosino BG Low-Density Lipoprotein Cholesterol Assay Kit (Direct Method-Surfactant Clearance Method); Biosino BG Glucose Assay Kit (Glucose Oxidase Method).

[0052] 2. Instruments

[0053] Multi-purpose low-temperature high-speed centrifuge, from Eppendorff, Germany; paraffin slicer, from Leica, Germany; frozen slicer, from Leica, Germany; En Vision multi-function microplate reader, from PerkinElmer Co., Ltd., USA; BD FACSMelody flow cytometer, from BD, USA; LE1305 respiratory metabolism analysis system, from Panlab.

[0054] 3. Animal Handling

[0055] Fourteen 8-week-old male C57BL / 6 mice, SPF grade; 27 8-week-old male ob / ob obese mice, SPF grade, were purchased from Beijing Weishang Lituo Technology Co., Ltd., license number: SCXK (Beijing) 2016-0009.

[0056] 2. Experimental Methods

[0057] 1. Animal Grouping and Rearing

[0058] Animals were housed in the Animal Experiment Center, Institute of Materia Medica, Chinese Academy of Medical Sciences under the following housing conditions: a barrier environment, a temperature of 22 ± 2°C, a humidity of 50%-60%, a 12 / 12 h day / night pattern, and ad libitum access to food and water.

[0059] After one week of adaptive feeding, C57BL / 6 mice were set as the control group (Control), and ob / ob obesity model mice were randomly divided into three groups: (1) Model group; (2) Exercise group (Exercise). Exercise method: Mice were screened after one week of adaptive feeding, and mice with strong exercise ability were selected. During this period, appropriate exercise training (10 m / min, 15 min) was given every other day; at the beginning of the experiment, mice in the exercise group received exercise training and ran at a speed of 15-18 m / min for 60 min per day, 5 days per week; (3) Experimental group (IMM-H007): IMM-H007 was administered once a day by gavage at a dose of 200 mg / kg body weight. All mice were fed with normal chow.

[0060] Mice were exercised or treated continuously for 8 weeks. Body weight and food intake were measured weekly. At 4 weeks of treatment, approximately 50 μL of blood was collected from the medial canthal vein to measure changes in blood lipids and determine the experimental endpoint.

[0061] 2. Observation indicators and measurement methods

[0062] 2.1 Serum biochemical indicators

[0063] The animals were fasted for 12 hours, and 0.5 ml of blood was collected from the medial angular vein. The blood was allowed to stand for 30 minutes and centrifuged at 2000 g for 10 minutes. As much supernatant as possible was aspirated, and serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and glucose levels were measured according to the instructions of the Zhongsheng Beikong blood lipid test kit.

[0064] Before the end of the experiment, the subjects were fasted overnight and anesthetized with 3% sodium pentobarbital intraperitoneally. The abdominal cavity was exposed and blood was collected from the abdominal aorta. The liver was quickly separated. One lobe of the liver was retained and a 1×1 cm piece was cut from the fixed position. 3 After cutting into small pieces, place them in 10% neutral formalin fixative and store at 4°C.

[0065] 2.2 Pathological staining of liver tissue

[0066] 2.2.1 Preparation of paraffin sections

[0067] After fixation with paraformaldehyde, rinse the liver with tap water and dehydrate according to the following steps: overnight in 70% ethanol, overnight in 80% ethanol, 30 minutes in 90% ethanol I, 30 minutes in 90% ethanol II, 60 minutes in 95% ethanol I, 60 minutes in 95% ethanol II, 60 minutes in 100% ethanol I, and 60 minutes in 100% ethanol II. Dehydration time can be extended for normal tissue. After dehydration, use Ultra-An clearing (Ultrasound I for 60 minutes, Ultra-An II for 60 minutes, and Ultra-An III for 60 minutes). For normal control livers, clearing time can be extended. Wax immersion at 65°C, followed by paraffin wax I for 50 minutes, paraffin wax II for 50 minutes, and paraffin wax III for 50 minutes, followed by embedding. Sections are 7 μm thick, unfolded at 45°C, and baked overnight at 50°C.

[0068] 2.2.2 Oil Red O staining

[0069] Frozen sections were fixed in neutral formalin solution for 10 min, rinsed with tap water for 2 min, rinsed with 60% isopropanol for 5 s, stained with 0.5% Oil Red O working solution in a light-proof staining box for 10 min, separated with 60% isopropanol for a few seconds, gently rinsed with tap water, counterstained with hematoxylin for 1 min, gently rinsed with tap water, mounted with glycerol gelatin, and observed under a microscope.

[0070] 2.2.3 HE staining

[0071] Paraffin sections were dehydrated as follows: Ultra-An I for 5 minutes, Ultra-An II for 5 minutes, Ultra-An III for 5 minutes, 100% ethanol I for 3 minutes, 100% ethanol II for 3 minutes, 95% ethanol I for 3 minutes, 95% ethanol II for 3 minutes, and 80% ethanol for 3 minutes. Rinsed with tap water for 1 minute. Hematoxylin staining was performed for 5 minutes, followed by a 1-minute rinse with tap water. Differentiation was performed with 1% hydrochloric acid and ethanol for several seconds. The sections were rinsed with tap water to return to blue. The sections were then rinsed with 80% ethanol for several seconds and eosin staining for 10 seconds. The sections were then toned with 80% and 95% ethanol. Dehydration was performed with 95% ethanol, 100% ethanol I, 100% ethanol II, Ultra-An I, Ultra-An II, and Ultra-An III for 2 minutes each. The sections were then mounted with ultra-clean high-grade mounting adhesive and observed under a microscope.

[0072] 2.2.4 Glucose tolerance

[0073] After six weeks of dosing, mice were fasted for 16 hours with or without water, and tail tip blood was collected to measure basal blood glucose. Subsequently, mice were gavaged with a 20% glucose solution (prepared in saline) at a dose of 2 g / kg body weight. Blood glucose concentrations were measured using a glucometer (Roche) at 30, 60, 90, and 120 minutes after the glucose loading.

[0074] 2.2.5 Oxygen consumption and energy detection

[0075] After eight weeks of exercise intervention or IMM-H007 treatment, ob / ob mice were placed in a metabolic monitoring system for 16 hours of pre-acclimatization. The respiratory entropy, gas changes (oxygen (VO2), carbon dioxide (VCO2), water vapor), as well as the mice's food intake, water intake, exercise status, energy expenditure (EE), etc. were simultaneously measured.

[0076] 2.2.6 Serum inflammatory factor detection

[0077] Eight weeks after dosing, blood was collected from the inner canthus of the eye after fasting for 12 hours. The blood sample was allowed to stand at room temperature for at least 30 minutes and then centrifuged at 2000 x g for 10 minutes at 4°C to collect serum. The serum was aliquoted and stored at -80°C until use.

[0078] According to the kit instructions, flow cytometry was used to detect the levels of serum inflammatory factors, and the levels of serum inflammatory factors reflected the level of inflammation in mice.

[0079] 2.3 Statistical analysis

[0080] All data are expressed as mean ± SE. The inventors used a two-tailed Student's t-test to compare data between two groups, and a one-way ANOVA and Tukey's post-hoc test to compare data from more than two groups. Differences between groups with non-normal distributions were compared using the Kruskal-Wallis sum-rank test and the Wilcoxon rank-sum test. Images were also analyzed for comparative analysis.

[0081] 3. Experimental Results

[0082] 3.1 Effects of IMM-H007 on blood lipid and blood glucose levels in mice

[0083] The results of blood lipid and blood glucose levels in mice are shown in Figure 1. The results showed that after four weeks of administration (Figure A), the serum TC, LDL-C, and glucose levels of the model group mice were significantly increased compared with the control group. Compared with the model group, exercise can significantly reduce the TC, TG, LDL-C, and glucose levels of obese mice. Treatment with IMM-H007 also significantly reduced the TC, TG, LDL-C, and glucose levels of obese mice.

[0084] After eight weeks of drug administration (Figure B), the serum TC, LDL-C and glucose levels of the model group mice were significantly increased compared with the control group; compared with the model group, the TC, TG, LDL-C and glucose levels of the exercise group mice were significantly decreased, and the TC, TG and LDL-C levels of the mice treated with IMM-H007 were also significantly decreased.

[0085] 3.2 IMM-H007 improves liver lipid accumulation in obese mice

[0086] The results of Oil Red O staining and HE staining are shown in Figure 2. The results of Oil Red O staining (Figure A) showed that the liver cells of the control group animals were arranged radially around the central vein, and the intracellular neutral fat content was low; there was a large amount of fat deposits in the liver cells of the model group animals, and vacuolation occurred; compared with the model group, the fat deposition in the liver cells of the exercise group and IMM-H007 group animals was significantly reduced.

[0087] HE staining (Figure B) showed that the liver cells of the control group animals were arranged radially around the central vein, and collagen fibers were regularly distributed in the central vein and other blood vessel walls; the liver cells of the model group animals showed vacuolation, and collagen fibers appeared between the liver cells, and the distribution was irregular; vacuoles appeared in the liver cells of the animals in the exercise group and the IMM-H007 treatment group, and collagen fibers appeared between the liver cells, and the distribution was irregular. The liver cells were arranged radially around the central vein, and collagen fibers were regularly distributed in the boundary area between the central vein and the hepatic lobule.

[0088] 3.3 IMM-H007 simulates exercise to slow weight gain in obese mice

[0089] The results of mouse weight changes are shown in Figure 3. As can be seen from the graph of mouse body weight changes over weeks (Figure A), compared with the control group, the weight of mice in the model group, exercise group, and IMM-H007 group increased slowly over time, and the change trend was consistent. As can be seen from the graph of mouse body weight gain over weeks (Figure B), compared with the control group, the weight of mice in the model group increased significantly; compared with the model group, the weight gain of mice in the exercise group and mice treated with IMM-H007 slowed down. As can be seen from the graph of average food intake of mice (Figure C), there was no significant difference in food intake among mice in the model group, exercise group, and IMM-H007 group.

[0090] 3.4 IMM-H007 improves glucose tolerance in obese mice

[0091] The results of glucose tolerance in mice are shown in Figure 4. The graph of blood glucose levels over time (Figure A) shows that blood glucose levels in the IMM-H007 group were significantly lower than in the model group. The glucose AUC (area under the curve) graph (Figure B) shows that glucose tolerance in the model group was impaired compared to the control group. Compared to the model group, oral glucose tolerance was significantly improved in the exercise group and in mice treated with IMM-H007.

[0092] 3.5 IMM-H007 increased oxygen consumption and energy expenditure in obese mice.

[0093] The results of the oxygen consumption and energy expenditure of mice are shown in Figure 5. From the graph of the changes in oxygen intake (VO2) over time (Figure A), the graph of the changes in carbon dioxide output (VCO2) over time (Figure B), and the graph of the changes in energy expenditure (EE) over time (Figure C), it can be seen that, regardless of light or dark conditions, the oxygen consumption and energy expenditure of the model group mice were significantly reduced compared with the control group, while the oxygen consumption of the exercise group mice and the mice treated with IMM-H007 was significantly increased, and the energy expenditure of the mice showed an increasing trend.

[0094] 3.6 IMM-H007 reduces serum inflammatory cytokine levels in obese mice

[0095] After eight weeks of exercise intervention or IMM-H007 treatment, the levels of serum inflammatory factors in obese mice were measured by flow cytometry, and the results are shown in Figure 6. The results showed that exercise and IMM-H007 treatment significantly reduced the serum concentrations of TNF-α (Figure A), IL-1α (Figure B), IL-1β (Figure C), and IFN-β (Figure D) serum inflammatory factors, thereby reducing the levels of these serum inflammatory factors.

[0096] In summary, triacetyl-3-hydroxyphenyladenosine (IMM-H007) can mimic exercise and improve obesity-related glucose and lipid metabolism disorders, significantly reducing serum TC, TG, LDL-C, and blood glucose levels in obese mice, slowing weight gain, improving glucose tolerance and hepatic lipid accumulation, increasing oxygen consumption, and reducing serum levels of inflammatory factors such as TNF-α, IL-1α, IL-1β, and IFN-β. These results suggest that IMM-H007 can be used to prepare exercise-mimicking drugs.

Claims

1. Use of triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof as represented by formula (I) in the preparation of motion-simulating drugs, 2. The use according to claim 1, characterized in that: The exercise is moderate-intensity aerobic exercise.

3. The use according to claim 1 or 2, characterized in that: The exercise-simulating drug produces an exercise-simulating effect in obese subjects, and the exercise-simulating effect is similar to the health effect produced by exercise; preferably, the exercise-simulating effect is to reduce serum TC, TG, LDL-C and glucose levels, slow down body weight gain, improve glucose tolerance, liver lipid accumulation, increase oxygen consumption, or reduce serum inflammatory factors TNF-α, IL-1α, IL-1β, IFN-β levels.

4. Use of a pharmaceutical composition in the preparation of a motion-simulating drug, the pharmaceutical composition comprising triacetyl-3-hydroxy-phenyladenosine or a pharmaceutically acceptable salt thereof represented by formula (I), and a pharmaceutically acceptable carrier or excipient, 5. The use according to claim 4, characterized in that: The exercise is moderate-intensity aerobic exercise.

6. The use according to claim 4 or 5, characterized in that: The exercise-simulating drug produces an exercise-simulating effect in obese subjects, and the exercise-simulating effect is similar to the health effect produced by exercise; preferably, the exercise-simulating effect is to reduce serum TC, TG, LDL-C and glucose levels, slow down body weight gain, improve glucose tolerance, liver lipid accumulation, increase oxygen consumption, or reduce serum inflammatory factors TNF-α, IL-1α, IL-1β, IFN-β levels.

7. The use according to any one of claims 1 to 6, characterized in that The medicine is in the form of tablets, capsules, pills and injections.

8. The use according to any one of claims 1 to 6, characterized in that The drug is a sustained-release preparation, a controlled-release preparation or various microparticle delivery systems.

9. The use according to any one of claims 1 to 6, characterized in that The administration route of the drug is selected from oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vaginal and rectal administration.

10. The use according to any one of claims 1 to 6, characterized in that The dosage of triacetyl-3-hydroxy-phenyladenosine or its pharmaceutically acceptable salt described in formula (I) is 0.001-250 mg / kg body weight, preferably 0.1-220 mg / kg body weight, more preferably 100-210 mg / kg body weight, and most preferably 150-200 mg / kg body weight.

11. A method for simulating exercise, comprising administering triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as represented by formula (I) to a subject in need thereof, wherein the pharmaceutical composition comprises triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient as represented by formula (I), 12. The method according to claim 11, characterized in that The exercise is moderate-intensity aerobic exercise.

13. The method according to claim 11 or 12, characterized in that: The method produces an exercise-simulating effect in obese subjects, and the exercise-simulating effect is similar to the health effect produced by exercise; preferably, the exercise-simulating effect is to reduce serum TC, TG, LDL-C and glucose levels, slow down body weight gain, improve glucose tolerance, liver lipid accumulation, increase oxygen consumption, or reduce serum inflammatory factors TNF-α, IL-1α, IL-1β, IFN-β levels.

14. The method according to any one of claims 11 to 13, characterized in that The administration route is selected from oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vaginal and rectal administration.

15. The method according to any one of claims 11 to 14, characterized in that The dosage of triacetyl-3-hydroxy-phenyladenosine or its pharmaceutically acceptable salt described in formula (I) is 0.001-250 mg / kg body weight, preferably 0.1-220 mg / kg body weight, more preferably 100-210 mg / kg body weight, and most preferably 150-200 mg / kg body weight.

16. Triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as represented by formula (I) for use in simulating exercise, wherein the pharmaceutical composition comprises triacetyl-3-hydroxyphenyladenosine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, 17. The triacetyl-3-hydroxyphenyladenosine of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16, characterized in that: The exercise is moderate-intensity aerobic exercise.

18. The triacetyl-3-hydroxyphenyladenosine of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 or 17, characterized in that: The triacetyl-3-hydroxyphenyladenosine or its pharmaceutically acceptable salt or pharmaceutical composition as shown in formula (I) produces an exercise simulation effect in obese subjects, and the exercise simulation effect is similar to the health effect produced by exercise; preferably, the exercise simulation effect is to reduce serum TC, TG, LDL-C and glucose levels, slow down body weight gain, improve glucose tolerance, liver lipid accumulation, increase oxygen consumption, or reduce serum inflammatory factors TNF-α, IL-1α, IL-1β, IFN-β levels.

19. The triacetyl-3-hydroxyphenyladenosine of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 16 to 18, characterized in that: The administration route is selected from oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vaginal and rectal administration.

20. The triacetyl-3-hydroxyphenyladenosine of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 16 to 19, characterized in that: The dosage of triacetyl-3-hydroxy-phenyladenosine or its pharmaceutically acceptable salt described in formula (I) is 0.001-250 mg / kg body weight, preferably 0.1-220 mg / kg body weight, more preferably 100-210 mg / kg body weight, and most preferably 150-200 mg / kg body weight.

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