(S)-β-aminoisobutyrate and its preparation method and application in obesity

Abstract

The present invention belongs to the field of pharmaceutical active technology, and specifically relates to (S)-β-aminoisobutyrate, a preparation method thereof, and an application in obesity. (S)-β-aminoisobutyrate has a structure as shown in Formula I: wherein R is a linear or branched C1-C14 alkyl group. (S)-β-aminoisobutyrate is prepared by an Fmoc protection esterification method, and the L-BAIBA molecule is esterified and protected so that it can smoothly enter the systemic circulation by fat-soluble diffusion, and then L-BAIBA is released by esterase hydrolysis, thereby achieving the effect of improving bioavailability and sustained release of L-BAIBA. (S)-β-aminoisobutyrate can be used as an efficient L-BAIBA substitute, and has broad application prospects and huge development value in the treatment and / or prevention of obesity.

Description

Technical Field

[0001] The invention belongs to the technical field of drug activity, and specifically relates to (S)-β-aminoisobutyrate and a preparation method thereof and application thereof in obesity. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Obesity is a chronic metabolic disease caused by multiple factors, with the main characteristics including an increase in the number of fat cells, an imbalance in the distribution of body fat, and localized fat deposition. This disease is usually divided into three levels: mild, moderate, and severe. Mild obesity refers to a body weight that is 20% to 30% higher than the standard, moderate obesity refers to a body weight that is 30% to 50% higher than the standard, and severe obesity refers to a body weight that is 50% higher than the standard. Obesity has many negative effects on human health, such as increasing the risk of cardiovascular disease, diabetes, hypertension, and other diseases, and also affects body image and self-confidence.

[0004] The occurrence of obesity is related to many factors, including genetic factors, socio-cultural and economic factors, neuropsychiatric factors, endocrine factors, etc. At present, the commonly used weight loss methods include: strengthening exercise, controlling diet, drugs and surgical treatment. At present, the use of weight loss drugs such as orlistat, benaglutide, liraglutide, semaglutide, phentermine / topiramate, green caserin and naltrexone / bupropion is still the main means of treating moderate or severe obesity. However, the use of the above drugs can cause various side effects, such as headache, nausea, vomiting, dizziness, fecal incontinence, etc., and is accompanied by the disadvantage of easy rebound after stopping the drug.

[0005] Exercise is considered one of the healthiest ways to lose weight. Studies have shown that exercise can increase plasma β-aminoisobutyric acid (BAIBA) levels. BAIBA can induce white fat browning and promote liver β-oxidation, and plasma BAIBA levels are negatively correlated with cardiometabolic risk factors. It has also been reported that BAIBA can induce the body's thermogenic program independently of the adrenergic activation pathway and is an activator that causes white fat browning. At the same time, it does not rely on changes in energy intake or physical activity levels, but instead changes basal oxygen consumption to reduce body fat. It can be said that BAIBA is a true "sports molecule." It should be pointed out that BAIBA is an endogenous non-protein amino acid with a molecular weight of 103.6Da. Among them, (S)-β-aminoisobutyric acid (L-BAIBA) is produced by the decomposition of valine, and (R)-β-aminoisobutyric acid (D-BAIBA) is produced by thymine metabolism. In addition to self-production of BAIBA, experiments have shown that supplementing BAIBA can also significantly increase plasma BAIBA concentrations and achieve weight loss effects.

[0006] However, as a non-protein amino acid, L-BAIBA has a large molecular polarity and poor lipid solubility, making it difficult to achieve transmembrane transport through lipid diffusion. Therefore, only long-term high-dose supplementation of L-BAIBA can have the effect of reducing obesity. TM and The recommended dosage of L-BAIBA is about 500 mg / day to achieve the effect of weight loss. However, health products are not commodities, and their safety and effectiveness are not guaranteed. In addition, due to the lack of necessary human experimental data, long-term large-dose supplementation of L-BAIBA still has huge risks and uncertainties. Summary of the invention

[0007] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide (S)-β-aminoisobutyrate and its preparation method and application in obesity. The present invention prepares (S)-β-aminoisobutyrate by Fmoc protection esterification method, esterifies and protects L-BAIBA molecules, allows them to smoothly enter the systemic circulation by fat-soluble diffusion, and then releases L-BAIBA by esterase hydrolysis, which can achieve the effect of improving bioavailability and sustained release of L-BAIBA. (S)-β-aminoisobutyrate can be used as an efficient L-BAIBA substitute, and has broad application prospects and huge development value in the treatment and / or prevention of obesity.

[0008] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0009] In a first aspect, a (S)-β-aminoisobutyrate is characterized by having a structure as shown in Formula I:

[0010] In the formula, R is a linear or branched C1-C14 alkyl group.

[0011] In a second aspect, a method for preparing the (S)-β-aminoisobutyrate as described in the first aspect, characterized in that it comprises the following steps:

[0012] S1, (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid and fatty alcohol are dissolved in a solvent, and an esterification reaction is carried out under the action of a carbodiimide compound and 4-dimethylaminopyridine to obtain an (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid ester intermediate;

[0013] S2, (S)-β-fluorenylmethoxycarbonylaminoisobutyrate intermediate is dissolved in a solvent, and the Fmoc group is removed under the action of an organic base to obtain (S)-β-aminoisobutyrate;

[0014] The structure of the (S)-β-fluorenylmethoxycarbonylaminoisobutyrate intermediate is shown in Formula II:

[0015]

[0016] Preferably, the solvent includes dichloromethane, ethyl acetate, tetrahydrofuran, toluene or N,N-dimethylformamide, the concentration of (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid dissolved in the solvent is 0.1-1 mol / L, and the concentration of (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid intermediate dissolved in the solvent is 0.1-1 mol / L.

[0017] Preferably, in step S1, the carbodiimide compound includes dicyclohexylcarbodiimide or diisopropylcarbodiimide, and the molar ratio of the carbodiimide compound to (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid is (1-1.2):1.

[0018] Preferably, in step S1, the esterification reaction is carried out under nitrogen protection, the reaction temperature is room temperature, and the reaction time is 3 to 5 hours.

[0019] Preferably, in step S2, the organic base is a mixture of ethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene or piperidine, and the molar ratio of the organic base to the (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid in step S1 is (1.5-2.5):1.

[0020] Preferably, in step S2, the temperature for removing the Fmoc group is room temperature, and the reaction time is 1 to 3 hours.

[0021] In a third aspect, the use of the (S)-β-aminoisobutyrate as described in the first aspect in the preparation of a drug for treating and / or preventing obesity.

[0022] Preferably, the obesity is caused by excessive body weight due to excessive calorie intake.

[0023] Preferably, the obesity includes mild obesity, moderate obesity and severe obesity.

[0024] The beneficial effects achieved by one or more technical solutions of the present invention are as follows:

[0025] The (S)-β-aminoisobutyrate is prepared by esterification reaction and deprotection reaction, with mild conditions and high reaction efficiency, and the (S)-β-aminoisobutyrate can reach more than 60%.

[0026] (S)-β-aminoisobutyrate can significantly reduce the body weight of mice with high-fat diet-induced obesity model and reduce fat deposition in the liver of model mice. The L-BAIBA content in plasma, white fat, brown fat, muscle, liver and other tissues or organs of mice administered with (S)-β-aminoisobutyrate is significantly increased, and the effect is better than direct administration of L-BAIBA under the same conditions. (S)-β-aminoisobutyrate releases L-BAIBA into the animal body, which is transported to the whole body through the systemic circulation and significantly accumulates in white fat, brown fat, muscle, liver, plasma, etc., achieving the effect of treating and / or preventing obesity. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0028] Figure 1 This is the weight curve of mice in the fat loss experiment of high-fat diet-induced obesity model mice in Example 5;

[0029] Figure 2 Comparison of the concentrations of serum indicators (A) alanine aminotransferase (ALT), (B) aspartate aminotransferase (AST), (C) high-density lipoprotein cholesterol (HDL-C), (D) low-density lipoprotein cholesterol (LDL-C), (E) total cholesterol (TC) and (F) triglycerides (TG) after the fat loss experiment in the high-fat diet-induced obesity model mice in Example 5;

[0030] Figure 3 This is a cross-sectional view of white fat and liver after the fat reduction experiment on the high-fat diet-induced obesity model mice in Example 5;

[0031] Figure 4 These are the aggregate concentrations of (A) plasma, (B) muscle, (C) white fat, (D) brown fat, (E) liver and (D) in L-BAIBA mice after the fat loss experiment in the high-fat diet-induced obesity model mice in Example 5. DETAILED DESCRIPTION

[0032] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0033] Example 1

[0034] Preparation of (S)-β-aminoisobutyric acid n-hexyl ester, the reaction route and steps are as follows:

[0035]

[0036] To a 50mL three-necked flask, add (S)-β-Fmoc-aminoisobutyric acid (1.00g, 3.07mmol), dichloromethane (DCM, 20mL), n-hexanol (0.38g, 3.69mmol), 4-dimethylaminopyridine (DMAP, 19mg, 0.15mmol) in sequence, and replace with nitrogen three times. Place the reaction system in a 0℃ cooling bath and stir for 5min, then add N,N'-dicyclohexylcarbodiimide (DCC, 0.70g, 3.38mmol) in batches. After addition, stir at room temperature for 4h under nitrogen protection. TLC detection shows that (S)-β-Fmoc-aminoisobutyric acid has basically disappeared. After the reaction is completed, water (10 mL) is added to quench the reaction, the organic phase is separated and collected, the aqueous phase is extracted with DCM (10 mL × 2), the organic phase is collected and combined, the organic phase is washed with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to dry the organic phase, filtered, and the organic phase is subjected to reduced pressure rotary distillation to remove DCM. The obtained crude product (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-hexyl ester can be directly used for the next step reaction. (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-hexyl ester is dissolved in tetrahydrofuran (THF, 20 mL), the reaction system is placed in a 0°C cooling bath, stirred for 5 min, and then piperidine (0.52 g, 6.15 mmol) is slowly added. After the addition is completed, it is stirred at room temperature for 2 h. TLC detection shows that (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-hexyl ester has basically disappeared. After the reaction was completed, tetrahydrofuran was removed by rotary distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: methanol: dichloromethane = 1:100-1:20), v / v) to obtain the target product (S)-β-aminoisobutyric acid n-hexyl ester (371 mg, yield 66%).

[0037] The characterization data of (S)-β-aminoisobutyric acid n-hexyl ester are as follows:

[0038] 1 H NMR (400 MHz, CDCl 3)δ4.10(td,J=6.7,1.3Hz,2H),2.97(dd,J=12.9,7.9Hz,1H),2.86(d,J=5.0Hz,1H),2.84-2.78(m,2H), 2.66-2.53(m,1H),1.70-1.58(m,2H),1.37-1.28(m,6H),1.18(d,J=7.1Hz,3H),0.89(t,J=6.8Hz,3H);

[0039] 13 C NMR (100 MHz, CDCl 3 )δ14.1,14.9,22.6,25.6,28.6,31.5,42.5,45.1,64.8,175.7;

[0040] Mass(Triple-quadrupole)m / z calcd.for C 10 H 22 NO 2 [M+H] + :188.16,found:188.20.

[0041] Example 2

[0042] Preparation of (S)-β-aminoisobutyric acid n-heptyl ester, the reaction route and steps are as follows:

[0043]

[0044] To a 50mL three-necked flask, add (S)-β-Fmoc-aminoisobutyric acid (1.00g, 3.07mmol), dichloromethane (DCM, 20mL), n-heptanol (0.43g, 3.69mmol), 4-dimethylaminopyridine (DMAP, 19mg, 0.15mmol) in sequence, and replace with nitrogen three times. Place the reaction system in a 0℃ cooling bath and stir for 5min, then add N,N'-dicyclohexylcarbodiimide (DCC, 0.70g, 3.38mmol) in batches. After addition, stir at room temperature for 4h under nitrogen protection. TLC detection shows that (S)-β-Fmoc-aminoisobutyric acid has basically disappeared. After the reaction is completed, water (10 mL) is added to quench the reaction, the organic phase is separated and collected, the aqueous phase is extracted with DCM (10 mL × 2), the organic phase is collected and combined, the organic phase is washed with saturated brine, and an appropriate amount of anhydrous sodium sulfate is added to dry the organic phase, filtered, and the organic phase is subjected to reduced pressure rotary distillation to remove DCM. The obtained crude product (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-heptyl ester can be directly used for the next step reaction. (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-heptyl ester is dissolved in tetrahydrofuran (THF, 20 mL), the reaction system is placed in a 0°C cooling bath, stirred for 5 min, and then piperidine (0.52 g, 6.15 mmol) is slowly added. After the addition is completed, it is stirred at room temperature for 2 h. TLC detection shows that (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-hexyl ester has basically disappeared. After the reaction was completed, tetrahydrofuran was removed by rotary distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: methanol: dichloromethane = 1:100-1:20), v / v) to obtain the target product (S)-β-aminoisobutyric acid n-heptyl ester (363 mg, yield 60%).

[0045] The characterization data of (S)-β-aminoisobutyric acid n-heptyl ester are as follows:

[0046] 1 H NMR (400 MHz, CDCl 3 )δ4.09(t,J=6.7Hz,2H),2.93(dd,J=12.9,7.8Hz,1H),2.80(dd,J=12.9,5.0Hz,1H),2.58-2.48(m,1H),1.67( s,2H),1.66-1.60(m,2H),1.36-1.30(m,4H),1.30-1.25(m,4H),1.16(d,J=7.1Hz,3H),0.89(t,J=6.7Hz,3H);

[0047] 13 C NMR (100 MHz, CDCl 3 )δ14.1,14.8,22.6,25.9,28.7,29.0,31.8,43.0,45.4,64.6,175.8;

[0048] Mass(Triple-quadrupole)m / z calcd.for C 11 H 24 NO 2 [M+H] + :202.17,found:202.20.

[0049] Example 3

[0050] Preparation of (S)-β-aminoisobutyric acid n-octyl ester, the reaction route and steps are as follows:

[0051]

[0052] To a 50mL three-necked flask, add (S)-β-Fmoc-aminoisobutyric acid (1.00g, 3.07mmol), dichloromethane (DCM, 20mL), n-octanol (0.43g, 3.69mmol), 4-dimethylaminopyridine (DMAP, 19mg, 0.15mmol) in sequence, and replace with nitrogen three times. Place the reaction system in a 0℃ cooling bath and stir for 5min, then add N,N'-diisopropylcarbodiimide (DIC, 0.43g, 3.38mmol) in batches. After the addition, stir at room temperature for 4h under nitrogen protection. TLC detection shows that (S)-β-Fmoc-aminoisobutyric acid has basically disappeared. After the reaction was completed, water (10 mL) was added to quench the reaction, the organic phase was separated and collected, the aqueous phase was extracted with DCM (10 mL × 2), the organic phase was collected and combined, the organic phase was washed with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to dry the organic phase, filtered, and the organic phase was subjected to reduced pressure rotary distillation to remove DCM. The obtained crude product (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-octyl ester can be directly used for the next step reaction. (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-octyl ester was dissolved in tetrahydrofuran (THF, 20 mL), the reaction system was placed in a 0°C cooling bath, stirred for 5 min, and then diethylamine (Et) was slowly added. 2 NH, 0.22g, 3.07mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.47g, 3.07mmol). After the addition, stir at room temperature for 2h. TLC detection shows that (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-octyl ester basically disappears. After the reaction is completed, tetrahydrofuran is removed by rotary distillation under reduced pressure. The crude product is purified by silica gel column chromatography (eluent is methanol: dichloromethane = 1:100 to 1:20), v / v), to obtain the target product (S)-β-aminoisobutyric acid n-octyl ester (446mg, yield 69%).

[0053] The characterization data of (S)-β-aminoisobutyric acid n-octyl ester are as follows:

[0054] 1 H NMR (400 MHz, CDCl 3 )δ4.09(t,J=6.7Hz,2H),2.92(dd,J=12.9,7.8Hz,1H),2.79(dd,J=12.9,5.1Hz,1H),2.57-2.46(m,1H),1.69- 1.58(m,2H),1.53(s,2H),1.39-1.30(m,4H),1.30-1.25(m,6H),1.16(d,J=7.1Hz,3H),0.88(t,J=6.8Hz,3H);

[0055] 13 C NMR (100 MHz, CDCl 3 )δ14.2,14.8,22.7,26.0,28.7,29.2,29.3,31.8,43.1,45.4,64.7,175.8;

[0056] Mass(Triple-quadrupole)m / z calcd.for C 12 H 26 NO 2 [M+H] + :216.19,found:216.20.

[0057] Example 4

[0058] Preparation of (S)-β-aminoisobutyric acid n-decyl ester, the reaction route and steps are as follows:

[0059]

[0060] To a 50mL three-necked flask, add (S)-β-Fmoc-aminoisobutyric acid (1.00g, 3.07mmol), dichloromethane (DCM, 20mL), n-decanol (0.58g, 3.69mmol), 4-dimethylaminopyridine (DMAP, 19mg, 0.15mmol) in sequence, and replace with nitrogen three times. Place the reaction system in a 0℃ cooling bath and stir for 5min, then add N,N'-diisopropylcarbodiimide (DIC, 0.43g, 3.38mmol) in batches. After addition, stir at room temperature for 4h under nitrogen protection. TLC detection shows that (S)-β-Fmoc-aminoisobutyric acid has basically disappeared. After the reaction was completed, water (10 mL) was added to quench the reaction, the organic phase was separated and collected, the aqueous phase was extracted with DCM (10 mL × 2), the organic phase was collected and combined, the organic phase was washed with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to dry the organic phase, filtered, and the organic phase was subjected to reduced pressure rotary distillation to remove DCM. The obtained crude product (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-decyl ester can be directly used for the next step reaction. (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-decyl ester was dissolved in tetrahydrofuran (THF, 20 mL), the reaction system was placed in a 0°C cooling bath, stirred for 5 min, and then diethylamine (Et) was slowly added. 2 NH, 0.22g, 3.07mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.47g, 3.07mmol). After the addition, stir at room temperature for 2h. TLC detection shows that (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid n-decyl ester basically disappears. After the reaction is completed, tetrahydrofuran is removed by rotary distillation under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: methanol: dichloromethane = 1:100 to 1:20), v / v), to obtain the target product (S)-β-aminoisobutyric acid n-decyl ester (457mg, yield 62%).

[0061] The characterization data of (S)-β-aminoisobutyric acid n-decyl ester are as follows:

[0062] 1 H NMR (400 MHz, CDCl 3 )δ4.09(t,J=6.7Hz,2H),2.93(dd,J=12.9,7.8Hz,1H),2.80(dd,J=12.9,5.1Hz,1H),2.61-2.48(m,1H),1.75( s,2H),1.67-1.59(m,2H),1.36-1.30(m,4H),1.29-1.25(m,10H),1.17(d,J=7.1Hz,3H),0.88(t,J=6.8Hz,3H);

[0063] 13 C NMR (100 MHz, CDCl3 )δ14.2,14.8,22.7,26.0,28.7,29.3,29.4,29.6,32.0,43.0,45.4,64.7,175.8;

[0064] Mass(Triple-quadrupole)m / z calcd.for C 14 H 30 NO 2 [M+H] + :244.22,found:244.10.

[0065] Example 5

[0066] 6-8 week old C57BL / 6J mice were randomly divided into 6 groups, including 1 group given a normal diet (i.e., CK group) and 5 groups given a high-fat diet-induced obesity model, with 10 mice in each group. Among them, obesity model group I (i.e., HFD group) was not given any drug; obesity model group II (i.e., BAIBA group), each mouse was intraperitoneally injected with 0.1 ml of L-BAIBA aqueous solution at a dose of 24 mg / kg / day; obesity model group III (i.e., Oct-BL group), each mouse was intraperitoneally injected with 0.1 ml of (S)-β-aminoisobutyric acid n-octyl ester in polyethylene glycol 300 / water (70 / 30, V / V) at a dose of 0.6 mg / kg / day; obesity model In group IV (i.e., Oct-BM group), each mouse was intraperitoneally injected with 0.1 ml of (S)-β-aminoisobutyric acid octyl ester in polyethylene glycol 300 / water (70 / 30, V / V) solution at a dose of 1.2 mg / kg / day; in group V (i.e., Oct-BH group), each mouse was intraperitoneally injected with 0.1 ml of (S)-β-aminoisobutyric acid octyl ester in polyethylene glycol 300 / water (70 / 30, V / V) solution at a dose of 2.4 mg / kg / day. The mice were kept and administered for a total of 8 weeks.

[0067] The body weight curves of mice in each group are shown in Figure 1 As shown. The average body weight of mice in the HFD group exceeded that of the CK group by 20%, and the obesity model was successfully established. The body weights of mice in the BAIBA group (P>0.1), Oct-BL group (P<0.01), Oct-BM group (P<0.0001), and Oct-BH group (P<0.001) decreased successively, and were all lower than those in the HFD group, indicating that (S)-β-aminoisobutyric acid n-octyl ester has a dose-dependent effect of reducing the body weight of obese mice. The dosage of the Oct-BL, Oct-BM, and Oct-BH groups was converted to L-BAIBA, and the dosage molar amount was 1 / 80, 1 / 40, and 1 / 20 of that of the BAIBA group, indicating that the weight loss effect of (S)-β-aminoisobutyric acid ester represented by (S)-β-aminoisobutyric acid n-octyl ester is more than 80 times better than that of L-BAIBA.

[0068] After the fat loss experiment of high-fat diet-induced obese mice, all mice were fasted overnight (12 hours), blood samples were collected from the eye sockets of the mice, and the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of the six groups of experimental mice were detected. Figure 2 As shown in the results, compared with the CK group, the total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentrations of HFD mice were significantly increased, while the high-density lipoprotein cholesterol (HDL-C) concentration was significantly decreased (P<0.05). In addition, the concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased (P<0.001), which once again confirmed the successful establishment of the obese model mice. After intervention with a specified dose of (S)-β-aminoisobutyric acid n-octyl ester, the TC, TG and LDL-C concentrations of Oct-BL, Oct-BM and Oct-BH groups were significantly decreased compared with the high-fat diet group. In addition, the HDL- concentrations of mice in the Oct-BM and Oct-BH groups were significantly increased (P<0.05), and the ALT and AST concentrations were basically restored to normal levels. In summary, (S)-β-aminoisobutyrate can improve the liver function and blood lipid indexes of high-fat diet-induced obese model mice, and has the effect of preventing and treating obesity.

[0069] After the fat loss experiment in high-fat diet-induced obese model mice was completed, all mice were fasted overnight (12 hours) and killed with an overdose of the anesthetic sodium pentobarbital. After dissection, white fat and liver were removed, sliced ​​and stained, and the morphology of white fat and liver was observed. Figure 3 The results of HE staining of white fat and oil red staining of liver sections of mice in different experimental groups are shown. In the CK group, the adipocytes were closely arranged, with the largest number of cells in the same field of view, a small area of ​​oil red staining of liver tissue, small or invisible lipid droplets, and normal hepatocyte morphology. In the HFD group, the adipocyte volume increased significantly, hepatocyte fatty degeneration occurred in the liver, the number of lipid droplets increased significantly and accumulated, and merged into large red lipid droplets. The situation of the BAIBA group was similar to that of the HFD group. Compared with the HFD group, the adipocytes of mice in each Oct-B group were reduced to varying degrees. The liver sections showed that the volume of red lipid droplets was significantly reduced and sparse, and they were unevenly distributed in small granules, and the hepatocyte fat was slightly degenerated. Among them, the morphology of adipose tissue and liver tissue in the Oct-BM and Oct-BH groups was close to that of the CK group, and the improvement effect was obvious. The above results show that (S)-β-aminoisobutyrate has the function of improving adipocyte hypertrophy, reducing adipose tissue and improving liver fat deposition in mice induced by a high-fat diet.

[0070] Taking (S)-β-aminoisobutyric acid n-octyl ester as an example, the effect of (S)-β-aminoisobutyric acid ester as a potential substitute for L-BAIBA was evaluated. Figure 4 As shown, after 8 weeks of treatment, the plasma L-BAIBA concentration in all treatment groups increased significantly. Specifically, compared with the HFD group, the BAIBA group increased by 23% (P=0.08), the Oct-BL group increased by 50% (P<0.01), the Oct-BM group increased by 59% (P<0.01), and the Oct-BH group increased by 77% (P<0.0001) to 479ng / g. In addition, supplementation with L-BAIBA or (S)-β-aminoisobutyric acid n-octyl ester over 8 weeks resulted in varying degrees of increase in L-BAIBA content in muscle, white fat, brown fat, and liver, while changes in the kidney were smaller. Compared with the HFD group, the L-BAIBA content in the white fat of mice in each treatment group increased significantly, of which the BAIBA group increased by 1.2 times, the Oct-BM group and the Oct-BH group increased by 1.7 times and 2.2 times, respectively. L-BAIBA was also significantly deposited in brown fat in mice in each treatment group.

[0071] In summary, (S)-β-aminoisobutyrate has the effect of reducing the body weight of mice with high-fat diet-induced obesity model, and its weight loss effect is more than 60 times that of L-BAIBA; (S)-β-aminoisobutyrate can improve the liver function and blood lipid indicators of mice with high-fat diet-induced obesity model, and it has the effect of preventing and treating obesity; (S)-β-aminoisobutyrate has the function of reducing fat volume, reducing adipose tissue and improving fat deposition in the liver of mice induced by high-fat diet; long-term administration of (S)-β-aminoisobutyrate can significantly increase the deposition of L-BAIBA in mouse plasma, white fat, brown fat, muscle and liver.

[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of a (S)-β-aminoisobutyrate in the preparation of a drug for treating and / or preventing obesity, wherein: (S)-β-aminoisobutyrate has the structure shown in Formula I: In the formula, R is a linear or branched C1-C14 alkyl group.

2. A use according to claim 1, characterized in that: The preparation method of (S)-β-aminoisobutyrate comprises the following steps: S1, (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid and fatty alcohol are dissolved in a solvent, and an esterification reaction is carried out under the action of a carbodiimide compound and 4-dimethylaminopyridine to obtain an (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid ester intermediate; S2, (S)-β-fluorenylmethoxycarbonylaminoisobutyrate intermediate is dissolved in a solvent, and the Fmoc group is removed under the action of an organic base to obtain (S)-β-aminoisobutyrate; The structure of the (S)-β-fluorenylmethoxycarbonylaminoisobutyrate intermediate is shown in Formula II: In step S1, the solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, toluene or N,N-dimethylformamide, the concentration of (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid dissolved in the solvent is 0.1-1 mol / L, and the concentration of (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid intermediate dissolved in the solvent is 0.1-1 mol / L; The carbodiimide compound is selected from dicyclohexylcarbodiimide or diisopropylcarbodiimide, and the molar ratio of the carbodiimide compound to (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid is (1-1.2):1; The esterification reaction is carried out under nitrogen protection, the reaction temperature is room temperature, and the reaction time is 3 to 5 hours; In step S2, the organic base is a mixture of ethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene or piperidine, and the molar ratio of the organic base to the (S)-β-fluorenylmethoxycarbonylaminoisobutyric acid in step S1 is (1.5-2.5):1; The temperature for removing the Fmoc group is room temperature, and the reaction time is 1 to 3 hours.

3. The use according to claim 1, characterized in that The obesity is caused by excessive body weight due to excessive calorie intake.

4. The use according to claim 1, characterized in that The obesity is selected from mild obesity, moderate obesity and severe obesity.

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