Application of 2-oxovaleric acid in the preparation of drugs for weight loss or control of weight gain
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-03
- Publication Date
- 2026-08-14
AI Technical Summary
已经批准的药物中，部分长期治疗肥胖的药物因会导致严重的副作用而使治疗效果及患者药物依从性受到限制
[0017]本发明发现，2-氧代戊酸能够降低机体对食物的获取意愿，并促进机体的能量消耗，从而发挥控制体重增加、减肥的作用。本领域技术人员知道，α-酮戊二酸是谷氨酰胺的前体物质和三羧酸循环的中间产物，参与机体能量代谢。本发明发现，虽然α-酮戊二酸与2-氧代戊酸化学结构类似，但是α-酮戊二酸雾化治疗后并没有明显的降低机体对食物的获取意愿和促进机体能量消耗的作用。因此，2-氧代戊酸具有开发成减肥或控制体重增加的药物的前景。
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Abstract
Description
Technical Field
[0001] This invention belongs to the fields of molecular biology and biochemistry, and relates to new uses of compounds, specifically the application of 2-oxovaleric acid in the preparation of drugs for weight loss or control of weight gain. Background Technology
[0002] With the continued rise in global obesity rates, obesity and related health problems have become a major challenge in the field of global public health. Obesity is not only closely related to chronic diseases such as cardiovascular disease, diabetes, and hypertension, but it may also affect the expression and function of various biomolecules in the body by altering metabolic pathways. Besides genetic factors, the main factors contributing to obesity are attributed to high-calorie diets and reduced energy expenditure. Therefore, improving appetite and energy expenditure to address obesity is of great significance.
[0003] Current clinical management of obesity primarily relies on three approaches: behavioral management, pharmacological intervention, and surgical procedures. Among approved medications, some long-term obesity treatments suffer from severe side effects, limiting their effectiveness and patient adherence. Surgical interventions, such as gastric bypass surgery, are unsuitable for all obese patients. Therefore, there is an urgent need to develop novel obesity treatment methods.
[0004] 2-Oxovaleric acid (α-ketovalerate, α-KV), also known as 2-pentanoic acid, has the molecular formula C5H8O3 and a molecular weight of 116.12. There are currently no reports on the use of 2-oxovaleric acid for the treatment of obesity. Summary of the Invention
[0005] The purpose of this invention is to provide the use of 2-oxovalerate in the preparation of drugs for weight loss or control of weight gain.
[0006] The above-mentioned objective of this invention is achieved through the following technical solution:
[0007] The application of 2-oxovaleric acid in the preparation of drugs for weight loss or control of weight gain.
[0008] Preferably, the drug uses 2-oxovalerate as the active ingredient and is formulated into a pharmaceutically acceptable dosage form using a pharmaceutically acceptable carrier or excipient.
[0009] More preferably, the carrier or excipient is a solid, liquid or semi-solid.
[0010] More preferably, the dosage form is an aerosol, inhaler, solution, suspension, emulsion, ointment, gel, or suppository.
[0011] A pharmaceutical composition for weight loss or control of weight gain, wherein the active ingredient contains 2-oxovalerate.
[0012] The use of the above-mentioned pharmaceutical composition in the preparation of drugs for weight loss or control of weight gain.
[0013] Preferably, the drug is formulated into a pharmaceutically acceptable dosage form using the pharmaceutical composition as the active ingredient and a pharmaceutically acceptable carrier or excipient.
[0014] More preferably, the carrier or excipient is a solid, liquid or semi-solid.
[0015] More preferably, the dosage form is an aerosol, inhaler, solution, suspension, emulsion, ointment, gel, or suppository.
[0016] Beneficial effects:
[0017] This invention discovers that 2-oxovalerate can reduce the body's desire for food and promote energy expenditure, thereby playing a role in controlling weight gain and promoting weight loss. Those skilled in the art know that α-ketoglutarate is a precursor of glutamine and an intermediate product of the tricarboxylic acid cycle, participating in the body's energy metabolism. This invention finds that although α-ketoglutarate and 2-oxovalerate have similar chemical structures, α-ketoglutarate nebulization therapy does not significantly reduce the body's desire for food or promote energy expenditure. Therefore, 2-oxovalerate shows promise for development into a drug for weight loss or controlling weight gain. Attached Figure Description
[0018] Figure 1 The data represent the food intake and energy expenditure levels of the mice in each group in Example 1.
[0019] Figure 2 The data represent the food intake and energy expenditure levels of mice in each group in Example 2.
[0020] Figure 3 The weight gain rate, food intake, and energy expenditure levels of mice in each group in Example 3 are shown. Detailed Implementation
[0021] The following describes the substantive content of the present invention in detail with reference to embodiments, but this does not limit the scope of protection of the present invention.
[0022] Example 1: Single intervention with 2-oxovalerate
[0023] I. Experimental Materials
[0024] 1. Laboratory animals
[0025] The DIO male mice used in this study, induced with high fat intake for 8 weeks, were purchased from Hunan Slack Jingda Laboratory Animal Company. All experimental mice in this study were C57BL / B6 mice. In this example, mice were fed a high-fat diet (derived from a 60% fat-energy diet, TestDiet58Y1, TestDiet, USA).
[0026] 2. Experimental reagents
[0027] 2-Oxovaleric acid (Sigma, catalog number 75950).
[0028] II. Experimental Methods
[0029] 1. Solution preparation
[0030] 2-Ovalbumin solution was prepared by freshly preparing a diluted 2-oxovalbumin solution using phosphate-buffered saline (PBS) at a concentration of approximately 4000 ng / L in the test environment.
[0031] 2. Modeling, grouping, and drug administration
[0032] Male DIO mice induced by high-fat diets for 8 weeks were randomly divided into two groups: a control group (n=4) in which cotton balls were placed in cages and mice could not access them, and PBS solution was added to the cotton balls for a single intervention; and a drug treatment group (n=4) in which cotton balls of the same size as those in the PBS group were placed in cages and mice could not access them, and 2-oxovalerate solution (ensuring an environmental concentration of approximately 4000 ng / L) was added to the cotton balls for a single intervention.
[0033] 3. Appetite evaluation
[0034] All mice were placed in individual cages to acclimatize to the environment. Food was removed but free access to water was maintained overnight. They were given pre-weighed high-fat diet and the initial food weight was recorded. According to the experimental design, PBS cotton balls were placed in the control group and 2-oxovalerate cotton balls were placed in the treatment group. The remaining food was collected and weighed at 1, 2, 3 and 4 hours at the intervention point, and the cumulative food intake at each time point was calculated.
[0035] 4. Energy Consumption Evaluation
[0036] Energy metabolism and activity levels in mice were monitored using a Comprehensive Lab Animal Monitoring System (CLAMS, Columbus Instruments). The experiment was conducted at an ambient temperature of 25°C, with mice having free access to food and water. The system automatically collected energy metabolism data. Initial energy expenditure in both groups of mice was monitored. On the second day, PBS or 2-oxovalerate cotton balls were added to each mouse's cage for continued monitoring. Data from 4 hours before and after the intervention were used for statistical analysis.
[0037] 5. Statistical Analysis
[0038] Data were analyzed using GraphpadPrism software for two-way ANOVA and significance testing. All data are expressed as mean ± standard error (Mean ± SEM).
[0039] III. Experimental Results
[0040] The results are as follows Figure 1 As shown in Table 1, compared with the control group, the food intake of mice in the treatment group was reduced ( Figure 1 (A) and energy consumption increases ( Figure 1 (B and C). This result indicates that 2-oxovalerate can effectively reduce appetite and promote energy expenditure in mice.
[0041] Table 1. Food intake and energy expenditure of mice in each group
[0042] Food intake over 4 hours (grams) Energy expenditure (kcal / hr) control group 1.784±0.197 0.453±0.039 Drug administration group 0.898±0.044*** 0.594±0.019*
[0043] Note: All values are expressed as mean ± SEM. ***, P < 0.001 compared with the PBS-treated control group; *, P < 0.05 compared with the PBS-treated control group.
[0044] Example 2: Comparative Experiment
[0045] α-Ketoglutaric acid (α-KG) is a precursor of glutamine and an intermediate in the tricarboxylic acid cycle. It has the molecular formula C5H6O5 and a molecular weight of 146.10. It is a white, fine crystalline powder at room temperature, and its structure is similar to that of 2-oxovalerate, the compound studied in this invention. Studies have reported that α-ketoglutaric acid participates in energy metabolism. This example aims to compare the single-dose efficacy of 2-oxovalerate and α-ketoglutaric acid.
[0046] I. Experimental Materials
[0047] 1. Laboratory animals
[0048] The DIO male mice used in this study, induced with high fat intake for 8 weeks, were purchased from Hunan Slack Jingda Laboratory Animal Company. All experimental mice in this study were C57BL / B6 mice. In this example, mice were fed a high-fat diet (derived from a 60% fat-energy diet, TestDiet58Y1, TestDiet, USA).
[0049] 2. Experimental reagents
[0050] 2-Oxovaleric acid (Sigma, catalog number 75950) and α-ketoglutarate (Sigma, catalog number 75890).
[0051] II. Experimental Methods
[0052] 1. Solution preparation
[0053] 2-Ovalburic acid solution was freshly prepared into a diluted 2-oxovalburic acid solution using phosphate-buffered saline (PBS). α-Ketoglutarate solution was freshly prepared into a diluted α-ketoglutarate solution using phosphate-buffered saline (PBS).
[0054] 2. Modeling, grouping, and drug administration
[0055] Male DIO rats induced with high-fat diets for 8 weeks were randomly divided into 3 groups (n=4), receiving PBS nebulization (control group), α-ketoglutarate (α-KG administration group) nebulization, and 2-oxovalerate (α-KV administration group) nebulization intervention, respectively. The environmental concentrations in the α-ketoglutarate and 2-oxovalerate nebulization groups were controlled at 4000±200 ng / L.
[0056] All three groups of mice received only one nebulization intervention.
[0057] 3. Appetite evaluation
[0058] All mice were placed in individual cages to acclimatize to the environment. Food was removed but free access to water was provided overnight. They were given a pre-weighed high-fat diet and the initial food weight was recorded. According to the experimental design, they were given PBS nebulization, α-ketoglutarate nebulization, and 2-oxovalerate nebulization interventions, respectively. The remaining food was collected and weighed at 1, 2, 3, and 4 hours at the intervention points, and the cumulative food intake at each time point was calculated.
[0059] 5. Evaluation of Energy Consumption Level
[0060] Energy metabolism and activity levels in mice were monitored using the Comprehensive Lab Animal Monitoring System (CLAMS, Columbus Instruments). The experiment was conducted at an ambient temperature of 25°C, with mice having free access to food and water. After a single nebulization intervention, mice in three groups were placed in metabolic cages, and the system automatically collected energy metabolism data.
[0061] 5. Statistical Analysis
[0062] Data were analyzed using GraphpadPrism software for two-way ANOVA and significance testing. All data are expressed as mean ± standard error (Mean ± SEM).
[0063] III. Experimental Results
[0064] The results are as follows Figure 2As shown in Table 2, compared with the control group, the mice in the 2-oxovalerate single-nebulization administration group had decreased appetite, while the α-ketoglutarate single-nebulization administration did not affect appetite. Figure 2 In mice receiving a single nebulized dose of 2-oxovalerate (A), energy expenditure also increased, while energy expenditure remained unchanged in mice receiving a single nebulized dose of α-ketoglutarate (A). Figure 2 (B and C). This result indicates that 2-oxovalerate has a strong effect on reducing appetite and promoting energy consumption in mice.
[0065] Table 2. Food intake and energy expenditure of mice in each group
[0066] Food intake over 4 hours (grams) Energy expenditure (kcal / hr) control group 1.728±0.157 0.394±0.052 α-KV administration group 0.932±0.047*** 0.533±0.017* α-KG administration group 1.658±0.129 0.387±0.034
[0067] Note: All values are expressed as mean ± SEM. *, P < 0.05 compared with the PBS-treated control group; ***, P < 0.001 compared with the PBS-treated control group.
[0068] Example 3: Long-term intervention with 2-oxovalerate
[0069] I. Experimental Materials
[0070] 1. Laboratory animals
[0071] The DIO male mice used in this study, induced with high fat intake for 8 weeks, were purchased from Hunan Slack Jingda Laboratory Animal Company. All experimental mice in this study were C57BL / B6 mice. In this example, mice were fed a high-fat diet (derived from a 60% fat-energy diet, TestDiet58Y1, TestDiet, USA).
[0072] 2. Experimental reagents
[0073] 2-Oxovaleric acid (Sigma, catalog number 75950).
[0074] II. Experimental Methods
[0075] 1. Solution preparation
[0076] 2-Ovalburic acid solution was prepared by freshly preparing a diluted 2-oxovalburic acid solution using phosphate-buffered saline (PBS) at a test environment concentration of approximately 4000 ng / L.
[0077] 2. Modeling, grouping, and drug administration
[0078] Male DIO mice induced with high-fat diets for 8 weeks were randomly divided into two groups: a control group (n=6) in which cotton balls were placed in cages inaccessible to the mice, and PBS solution was added to the cotton balls. The intervention lasted for one hour daily for 8 weeks. The drug treatment group (n=6) in which cotton balls of the same size as those in the PBS group were placed in cages inaccessible to the mice, and 2-oxovalerate solution (ensuring an environmental concentration of approximately 4000 ng / L) was added to the cotton balls. The intervention lasted for one hour daily for 8 weeks.
[0079] 3. Appetite evaluation
[0080] When the average weight difference between the control group and the treatment group was about 1g but not statistically significant, all mice were placed in separate cages to adapt to the environment. Food was removed but free access to water was maintained overnight. The mice were given pre-weighed high-fat feed and the initial food weight was recorded. The remaining food was weighed 1, 2, 3 and 4 hours after the feed was added, and the cumulative food intake at each time point was calculated.
[0081] 4. Evaluation of Energy Consumption Level
[0082] When the average body weight difference between the control group and the treatment group was approximately 1 g but not statistically significant, the energy metabolism and activity level of the mice were monitored using a Comprehensive Lab Animal Monitoring System (CLAMS, Columbus Instruments). The experiment was conducted at an ambient temperature of 25°C, with mice having free access to food and water. The system automatically collected energy metabolism data and monitored the mice continuously for 3 days. Data from days 2 and 3 were used for statistical analysis.
[0083] 5. Statistical Analysis
[0084] Data were analyzed using GraphpadPrism software for two-way ANOVA and significance testing. All data are expressed as mean ± standard error (Mean ± SEM).
[0085] III. Experimental Results
[0086] The results are as follows Figure 3 As shown in Table 3, the weight gain of mice in the treatment group was significantly less than that of mice in the control group. Figure 3 In mice with type A, appetite was significantly reduced compared to the control group. Figure 3 In mice B, energy consumption was significantly increased compared to the control group. Figure 3 (C and D in the original text). This result indicates that 2-oxovalerate can effectively reduce appetite in mice, promote energy expenditure, and control weight gain.
[0087] Table 3. Food intake, energy expenditure, and body weight of mice in each group.
[0088] Weight gain rate % Food intake over 4 hours (grams) Energy expenditure (kcal / hr) control group 11.686±0.459 1.83±0.118 0.499±0.034 Drug administration group 8.727±0.527** 1.103±0.073*** 0.566±0.036*
[0089] Note: All values are expressed as mean ± SEM. *, P < 0.05 compared with the PBS-treated control group; **, P < 0.01 compared with the PBS-treated control group; ***, P < 0.001 compared with the PBS-treated control group.
[0090] In summary, 2-oxovalerate can reduce the body's desire for food and promote energy expenditure, thereby playing a role in controlling weight gain and promoting weight loss. Those skilled in the art know that α-ketoglutarate is a precursor of glutamine and an intermediate product of the tricarboxylic acid cycle, participating in energy metabolism. This invention has found that although α-ketoglutarate and 2-oxovalerate have similar chemical structures, α-ketoglutarate treatment does not significantly reduce the body's desire for food or promote energy expenditure. Therefore, 2-oxovalerate shows promise for development into a drug for weight loss or controlling weight gain.
[0091] The purpose of the above embodiments is to specifically illustrate the substantive content of the present invention, but those skilled in the art should know that the scope of protection of the present invention should not be limited to the specific embodiments.
Claims
Application of 1,2-oxovalerate in the preparation of drugs for weight loss or control of weight gain.
2. The application according to claim 1, characterized in that: The drug uses 2-oxovalerate as the active ingredient and is formulated into a pharmaceutically acceptable dosage form using a pharmaceutically acceptable carrier or excipient.
3. The application according to claim 2, characterized in that: The carrier or auxiliary material is a solid, liquid or semi-solid.
4. The application according to claim 2, characterized in that: The dosage form is an aerosol, inhaler, solution, suspension, emulsion, ointment, gel, or suppository.
5. A pharmaceutical composition for weight loss or controlling weight gain, characterized in that: The active ingredient contains 2-oxovalerate.
6. Use of the pharmaceutical composition of claim 5 in the preparation of a medicament for weight loss or control of weight gain.
7. The application according to claim 6, characterized in that: The drug uses the pharmaceutical composition as the active ingredient and is formulated into a pharmaceutically acceptable dosage form using a pharmaceutically acceptable carrier or excipient.
8. The application according to claim 7, characterized in that: The carrier or auxiliary material is a solid, liquid or semi-solid.
9. The application according to claim 7, characterized in that: The dosage form is an aerosol, inhaler, solution, suspension, emulsion, ointment, gel, or suppository.