KR20070001326A - Novel ligand of nuclear receptor ppar gamma - Google Patents

Abstract

A novel ligand of a nuclear receptor PPARgamma is provided to control expression of genes related to sugar metabolism by activating PPARgamma, promote adipocyte differentiation by maximizing sugar-receiving ability of preadipocyte, and reduce sugar level in blood, so that it is useful for prevention and treatment of type II diabetes. The ligand of the nuclear receptor PPARgamma contains macelignan represented by the formula(1) or its pharmaceutically acceptable salt. A pharmaceutical composition for prevention and treatment of disease capable reacting with activation of nuclear receptor PPARgamma comprises the macelignan represented by the formula(1) or its pharmaceutically acceptable salt, wherein the disease reacting with activation of nuclear receptor PPARgamma is type II insulin-tolerant diabetes.

Description

Novel ligand of nuclear receptor PPAR gamma

1 is a process diagram for separating maceignan from Myristica fragrans .

Fig. 2 is the ¹³ C-NMR spectrum of the mace league of the present invention.

Figure 3 is a ¹ H-NMR spectrum of the mace league of the present invention.

Fig. 4 is the ¹ H- ¹ H COSY spectrum of the mayis lignan of the present invention.

Figure 5 is a ¹ H- ¹³ C HMBC spectrum of the maye lignan of the present invention.

Fig. 6 is the EI-Mass spectrum of the mace league of the present invention.

7 is a chemical structural formula of the mace league of the present invention.

FIG. 8 is a graph measuring the concentration of the mace lignan of the present invention activated by binding to PPARγ.

Fig. 9 shows the results of investigating the effect of the Mays lignan of the present invention increasing the expression of the target gene of PPARγ.

10 is a result of promoting the differentiation of adipocyte differentiation of 3T3-L1 rat fibroblasts cultured by the Mays lignan of the present invention by activating PPARγ.

The present invention relates to a medicament for the treatment or prevention of a disease in response to the activation of the PPARγ (Peroxisome Proliferator Activated Receptor γ) receptor, more specifically, the mayelignan (macelignan) represented by the formula (I) Expression of genes involved in metabolism was regulated, fat cell differentiation was promoted by maximizing glucose capacity of all cells, and blood glucose was reduced in obese / diabetic mouse models.

[Formula I]

Diabetes can be roughly divided into type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease caused by genetic susceptibility and viral infections resulting in an immunological response to the pancreas and selective destruction of β-cells. to be. Type 2 diabetes is the leading type of insulin resistance. The main etiologies include reduced insulin receptors, reduced tyrosine kinase activity, reduced muscle and adipose tissue type transporters, and insulin receptor substrate-1 (IRS-1). Has been reported to be caused by complex causes such as intracellular deficiency. Type 2 diabetes occurs mainly in adults and accounts for 90% of all diabetes ( Drugs , 65: 433-445, 2005).

Peroxysomes are micro-organs that are involved in the oxidation of cells and oxidize fatty acids in the cells to make hydrogen peroxide and neutralize toxic substances. In addition, it has a function of catalase, an oxidase, to decompose excess hydrogen peroxide produced in cells into water and oxygen. Perxisome proliferator is a generic name for compounds that can increase the number of peroxysomes, and fats, fatty acids and fibrate and prostaglandin are known to treat hyperlipidemia (Pharmacological Research, 5: 85-94). , 2005). Intranuclear receptors containing such peroxysomal proliferation agents as ligands are called PPARs, and there are three kinds of α, δ, and γ.

PPARα is mainly expressed in the liver and is involved in the oxidation of fatty acids or neutralization of toxic substances and is involved in inflammatory responses. PPARδ is evenly distributed and its action is uncertain. PPARγ is known as a central regulator of adipocyte differentiation. Recently, the expression of PPARγ was increased during the differentiation of adipocytes into adipocytes, and fibroblasts were reported to differentiate into adipocytes when PPARγ was expressed in fibroblasts with no differentiation ability ( Annu. Rev. Med., 53: 409-435, 2002). In addition, the activation of PPARγ maximizes the adipocyte capacity of adipocytes, promotes adipocyte differentiation and decreases insulin resistance ( Tren. Pharmacol. Sci., 25: 331-336, 2004). Thus, representative ligands of PPARγ may serve as therapeutic agents for type 2 diabetes due to insulin resistance. For example, TZD drugs, such as troglitazone, pioglitazone and rosiglitazone, are currently used as type 2 diabetes drugs that reduce insulin resistance as a representative ligand of PPARγ.

Despite the superiority of antidiabetic drugs aimed at adipocyte differentiation and PPARγ, few studies have been conducted on the development of natural substances. TZD-based drugs of synthetic products are known to have fewer side effects than other diabetic drugs, but there are still many problems to be solved because they are known to cause side effects such as hepatotoxicity and obesity. Therefore, the detection of PPARγ ligands in natural products with less side effects and toxicity is very important for the prevention and treatment of type 2 diabetes.

Myristica fragrans is a perennial plant grown in the tropics and its fruit, known as mace or nutmeg, has long been used as a spice. Mays lignan is a representative lignan compound found in Myristica fragrances ( Phytochemistry , 26: 1542-1543, 1987). It has been shown to enhance caspase-3 activity inducing apoptosis ( Biol. Pharm. Bull . , 27: 1305-1307, 2004), antimicrobial activity against oral microorganisms (Korean Patent Publication No. 10-2005-0035954), inhibitory effect on brain cell lipid peroxidation and free radical production ( Biochem. Biophys. Res. Commu. , 331 1264-1269).

However, no studies have been reported on the anti-diabetic use of Mayslignan targeting PPARγ. Therefore, the present inventors searched for various kinds of natural products to find an active substance that can treat or prevent insulin-resistant type 2 diabetes in response to PPARγ activity, and mayis lignan isolated from mystica fragrance activates PPARγ. The present invention was completed by elucidating the effects of treating and preventing type 2 diabetes.

It is an object of the present invention to provide the use of mayis lignan isolated from myritica fragrance in the treatment or prevention of diseases responsive to activation of the PPARγ receptor, for example type 2 insulin resistant diabetes.

In accordance with the above object, the present invention is a disease that reacts to the activation of the ligand and PPARγ receptor of PPARγ receptor containing mayis lignan or a pharmaceutically acceptable salt thereof represented by the following formula (I), for example type 2 It provides a pharmaceutical composition for the treatment or prevention of diabetes.

[Formula I]

Hereinafter, the present invention will be described in more detail.

The present invention is characterized by providing a novel use of mayis lignan isolated from Myristica fragrance extract.

Mace lignan having antidiabetic activity by activating PPARγ of the present invention can be isolated and purified from myristica fragrance using a method of extracting and separating conventional substances. Preferably, it can be separated and purified from nutmeg or ail. It can also be isolated and purified from other nutmeg plants, M yristica argentea warb ( Nat. Prod. Lett ., 16: 1-7, 2002), Machilus thunbergii ( Bio Pharm. Bull ., 27: 1305-1307, 2004), Leucas aspera , and the like, can also be isolated and purified ( Chem. Pharm. Bull ., 51: 595-598, 2003).

The mayis lignan of the present invention can be obtained by a conventional extraction and separation method. First, the dried mystica fragrance is placed in an extraction apparatus with 4 to 10 times of extraction solvent and left to extract for 2 days, and the concentrate is concentrated. Concentrate and dry to obtain an extract. In the present invention, as an extraction solvent for separation, water or an organic solvent of C1-C6 may be used. Preferably, purified water, methanol (methanol), ethanol, ethanol, propanol, isopropanol, butanol ( butanol, acetone, ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, petroleum ether Various solvents, such as (petroleum ether), can be used individually or in mixture. The extract obtained as described above may obtain a fraction according to polarity using silica gel column chromatography, and may separate the mayis lignan from the separated specific fraction through reverse phase column chromatography and high performance liquid chromatography (HPLC). However, the extraction and separation and purification method of the active ingredient is not necessarily limited to the above method.

PPARγ is a group of nuclear receptors known to play a role in regulating gene expression important for fat and glucose metabolism. In particular, PPARγ is believed to be involved in adipocyte differentiation and insulin action. When combined with ligand, PPARγ forms a heterozygote with retinoid X receptor alpha (RXRα) to increase the transcription rate of genes with peroxisome proliferator responsive element (PPRE) such as adipocyte P2 (aP2) or phosphoenolpyruvate carboxykanse (PEPCK). . Thiazolidinediones (TZD), known as a representative ligand of PPARγ, is an antidiabetic group that improves insulin resistance. ( Diabetes, 45: 1661-1669, 1996; Diabetes Care, 15: 193-203, 1992). TZD, a ligand of PPARγ, has a hypoglycemic effect in animal models of obesity, obesity and type 2 diabetes, but is not effective in diabetic patients with normal or insulin deficiency. have. Therefore, the discovery of ligands of PPARγ is known as a suitable invention for the prevention and treatment of type 2 diabetes resulting from insulin resistance. In an embodiment of the present invention, it was investigated whether the maye lignan of the present invention binds as a ligand to activate PPARγ. As a result, the mayis lignan of the present invention increased the concentration-dependent activation in conjunction with PPARγ (see Fig. 8).

LPL (lipoprotein lipase) and PEPCK (phosphoenol pyruvate carboxykinase) are the target genes of PPARγ. Allow sugar to be stored as triglycerides. Therefore, these two genes are directly regulated by PPARγ and are important genes for diabetes to allow fat cells to absorb free fatty acids and sugars present in the blood. Therefore, in another embodiment of the present invention, it was examined whether the maye lignan of the present invention activates PPARγ to increase the expression of LPL and PEPCK genes, which are target genes. As a result, it was confirmed that the maye lignan of the present invention increases the mRNA expression of LPL and PEPCK (see FIG. 9).

It is known that the greater the activation of PPARγ, the greater the adipocyte capacity of adipocytes and promote the differentiation of adipocytes ( Trends in Pharmacological Sciences, 25: 331-336, 2004). Therefore, in another embodiment of the present invention, it was investigated whether the mace lignan of the present invention promoted adipocyte differentiation by activating PPARγ. As a result, it was confirmed that the mace lignan of the present invention promotes fat granularity of 3T3-L1 which is all-cell cells (see FIG. 10).

Obesity / diabetic mice (ob / ob mouse) due to the lack of leptin (leptin) gene is not appetite is regulated to continue to excessive food intake. As a result, fat is excessively accumulated in the body, and at about 3 months after birth, it maintains around 50g, which is twice the weight of a typical mouse. It is also a model of typical type 2 diabetes with higher blood sugar levels compared to normal mice ( Exp. Clin. Endocrinol. Diabetes , 109: 307-319, 2001). These obese / diabetic mice are representative experimental animal models used to explore anti-obesity and anti-diabetic and therapeutic agents or to evaluate anti-obesity and anti-diabetic efficacy. The mayis lignan of the present invention was found to be effective in treating or preventing type 2 diabetes by significantly reducing blood glucose in an obese / diabetic mouse model.

Thus, the mayis lignan of the present invention is a ligand of PPARγ that increases insulin sensitivity, activates PPARγ to increase the expression of target genes accordingly, and induces adipocyte differentiation by increasing the ability to absorb sugar in adipocytes. In addition, the hypoglycemia was significantly reduced in obese / diabetic mouse model, suggesting the type 2 diabetes inhibition effect.

Mayes lignans according to the invention may be used in the form of salts, preferably pharmaceutically acceptable salts. The salt is preferably an acid addition salt formed with a pharmaceutically acceptable free acid. Organic acids and inorganic acids may be used as the free acid. The organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid. In addition, the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.

When administered clinically for the purpose of treating insulin resistant type 2 diabetes, the compositions of the present invention may be formulated into unit dosage forms suitable for oral or parenteral administration. When formulated in the form of a general medicine, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like. Are mixed to prepare. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, ointments, creams. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

In addition, the composition of the present invention can be administered parenterally, parenteral administration is by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection injection method. To formulate into a parenteral formulation, mayis lignan is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is formulated in unit dosage forms of ampoules or vials. Dosage units may contain, for example, one, two, three or four times, or 1/2, 1/3 or 1/4 times the individual dosage. The individual dosage preferably contains an amount in which the effective drug is administered at one time, which usually corresponds to all, 1/2, 1/3 or 1/4 times the daily dose. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method and excretion, drug combination and severity of the disease.

As a result of conducting oral toxicity test of the maye lignan of the present invention to rats, the 50% lethal dose (LD ₅₀ ) by oral toxicity test was found to be 2,000 mg / kg or more.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto. In addition, all activity assays were repeated three or more times and the results were expressed as mean ± standard deviation.

Example 1 Isolation and Purification of Mayslignan from Myristica Fragrance

<1-1> Isolation and Purification of Mace Lignan

400 ml of 75% methanol was added to 100 g of dry ground nutmeg and left to stand at room temperature for two days. The extracted solution was filtered and concentrated in vacuo to prepare a nutmeg methanol extract (7 g), which was partitioned between ethyl acetate, butanol and water. The ethyl acetate fraction (4.2 g) was eluted with a solvent in which hexane and ethyl acetate were mixed at a ratio of 10: 1 (v / v) using silica gel column chromatography to obtain fraction III (1 g). Fraction III was column chromatographed with a solvent mixed with hexane and ethyl acetate at a ratio of 20: 1 (v / v) to give fraction III-B (0.52 g). Subsequently, fraction III-B was eluted with 80% methanol using Rp-18 column chromatography to obtain single substance fraction III-B-2 (0.5 g). Such a separation process chart is shown in FIG. 1 .

<1-2> Structure Analysis

In order to determine the structure of the isolated single material III-B-2, ¹ H-NMR spectrum and ¹³ C-NMR spectrum were measured at 600 MHz and 150 MHz (solvent: DMSO), respectively. The results are shown in FIGS . 2 and 3 , respectively. ¹³ C-NMR spectrum and the ^{1 H-NMR 1 H- 1 H} COSY spectrum and ¹ H- ¹³ to measure the correlation of the correlation of the ¹ H- ¹ H, based on the result of the spectrum related to the ¹ H- ¹³ C HMBC C The spectrum was measured. The results are shown in FIGS . 4 and 5 , respectively. ^{The results of 1} H-NMR, ¹³ C-NMR, ¹ H- ¹ H COZY, and ¹ H- ¹³ C HMBC were comprehensively analyzed and shown in Table 1 .

Position 13C-NMR 1H-NMR 1H-1H COSY 1H-13C HMBC One 135.4 2 109.2 6.72 brs C-7, C-6, C-4, C-3 3 147.3 4 145.1 5 107.9 6.79 d (7.8) 6.61 C-6, C-4, C-3, C-1 6 121.7 6.61 dd (7.8) 6.79 C-7, C-5, C-4, C-2, C-1 7 38.2 2.23 dd (13.2, 9.3) 2.66 dd (13.2, 4.8) 1.64, 2.66 1.64, 2.23 C-8, C-6, C-2, C-1 C-9, C-8, C-6, C-2, C-1 8 38.7 1.64 brs 0.75, 2.23, 2.66 C-7 9 16.0 0.75 d (6.3) 1.64 C-8, C-7 One' 132.4 2' 112.9 6.66 brs C-7 ', C-6', C-4 ', C-3' 3 ' 147.1 4' 144.4 5 ' 115.2 6.66 d (7.9) 6.53 C-6 ', C-4', C-3 ', C-1' 6 ' 121.0 6.53 d (7.9, 1.1) 6.66 C-7 ', C-5', C-4 ', C-2', C-1 ' 7 ' 38.0 2.17 dd (13.2, 9.3) 2.66 dd (13.2, 4.8) 1.64, 2.66 1.64, 2.17 C-8 ', C-6', C-2 ', C-1' C-9 ', C-8', C-6 ', C-2', C-1 ' 8' 38.7 1.64 brs 0.75, 2.17, 2.66 C-7 ' 9 ' 16.1 0.75 d (6.3) 1.64 C-8 ', C-7' OMe 55.5 3.72 (s) O-CH2-O 100.6 5.95 d (4.8) C-3, C-4

<1-3> mass spectrometry

The results of EI / MS measured for mass spectrometry of the separated single substance are shown in FIG. 6 . The compound had a molecular weight of 328 with [M] ⁺ being observed at m / z 328 in EI / MS, and the molecular formula was C ₂₀ H ₂₄ O ₄ .

<1-4> Non-photon measurement

20 mg of the separated single substance III-B-2 was dissolved in 2 ml of chloroform (CHCl ₃ ), and then the specific light intensity ([α] _D ) value was measured by a polarimeter (Automatic Polarimeter, APIII-589, Rodulph, NJ, USA). [α] _D = +4.0 (CHCl ₃ , c = 1.0).

The results of the above ¹ H-NMR, ¹³ C-NMR, ¹ H- ¹ H COZY, ¹ H- ¹³ C HMBC, EI / MS and [α] _D and previously published research reports (Woo, WS et al . , Phytochemistry , 26: 1542-1543, 1987) was identified as a result, it was confirmed that the isolated single substance is macelignan ( Fig. 7 ).

Example 2 Activation of PPARγ by Mays Lignan

Finding a ligand that binds to PPARγ and causes activation of a gene having a PPARγ response sequence (PPRE), experiments using a plasmid expressing PPARγ and a vector having a luciferase gene under PPRE control are known. ( Cell, 68: 879-887, 1992; J. Biol. Chem., 272: 25252-25259, 1997) Activation of luciferase expression transfects COS-7 monkey kidney cells with PPARγ plasmid and pFR-luciferase vector. After the treatment, the mace lignan of the present invention was measured for 24 hours. At this time, the treatment with the mayis lignan of the present invention by concentration (1, 5, 10 and 25 μM) together with 0.01% DMSO treatment as a control, and known compounds used in the treatment of type 2 insulin resistance diabetes, namely troglitazone It was compared with the activity of (TZD).

As shown in FIG. 8 , mayis lignan increased PPARγ activity in a concentration-dependent manner, and showed a significant difference (*, p <0.01) when compared to the control at all concentrations treated. For example, when treated with 25 μM each, the activity of the comparative compound troglitazone was about 8.3 times higher than that of the control, while the luciferase activity induced by the maye lignan of the present invention was about 10.4 times higher than the control. This means that mayis lignan of the present invention not only activated PPARγ as a ligand of PPARγ, but also was more efficient in activating the PPARγ receptor than troglitazone, which is a conventional drug.

Example 3 Expression of Target Gene by PPARγ Activation

3T3-L1 mouse cell cells cultured in DMEM medium containing 10% FBS were incubated for 5 hours at 1 × 10 ⁶ cells. Mace lignan of the present invention was added to the cultured cells at 10 μM and allowed to stand for 24 hours. The cultured cells were cultured with MDI (0.5 mM 3-isobutyl-1-metylxanthine, 0.5 uM dexamethasone, 10 ug / ml insulin) medium to induce adipocyte differentiation ( Am. J. Physiol. Cell Physiol., 280 : C807-C813, 2001). Cells were obtained after 2 days from the time when the MDI medium was added. The obtained cells were isolated from total RNA using TRIZOL (Invitrogen, USA). Total RNA isolated was quantified and synthesized cDNA for 20 minutes at 42 ℃ using reverse transcriptase and 1 minute at 95 ℃, 56 ℃ 30 seconds, 72 ℃ 2 using Primer (LPL and PEPCK) and Taq Polymerase prepared earlier. RT-PCR was performed for 30 minutes.

As a result, as shown in Figure 9 , mRNA expression of the target genes LPL and PEPCK, which is increased by PPARγ activity is significantly higher than the control group when treated with mayis lignan at each concentration (*, p <0.01; **, p <0.05) increased. This means that the mayis lignan of the present invention can activate PPARγ to regulate expression of target genes of PPARγ, which are important for glucose metabolism.

Example 4 Promoting Adipocyte Differentiation According to PPARγ Activity

3T3-L1 mouse cell cells cultured in DMEM medium containing 10% FBS were incubated for 5 hours at 1 × 10 ⁶ cells. Mayes lignan of the present invention was added to the cultured cells in concentrations (1, 5, 10 and 25 μM), respectively, and left for 24 hours. The cultured cells were cultured with MDI (0.5 mM 3-isobutyl-1-metylxanthine, 0.5 uM dexamethasone, 10 ug / ml insulin) medium to induce adipocyte differentiation ( Am. J Physiol. Cell Physiol. , 280: C807-C813, 2001). Two days after the addition of the MDI medium, the morphology of the cells was observed under an optical microscope.

As a result, as shown in Fig. 10 , it was found that the adipocytes treated with mace lignan were promoted in the differentiation of adipocytes compared with the control and troglitazone. This means that the maye lignan of the present invention activated PPARγ to maximize adipocyte absorption of adipocytes and promoted adipocyte differentiation.

Example 5 Antidiabetic Effect of Mayslignan in Obese / Diabetes Mouse Model

  Obesity / diabetic mice (ob / ob mouse) used as a diabetic model animal is inadequately controlled due to a deficiency of leptin genes, resulting in excessive food intake. As a result, fat is excessively accumulated in the body and becomes a model of the typical type 2 diabetes which has a high blood sugar level compared with a normal mouse. Therefore, in order to investigate the prevention and treatment effect of diabetes, four mature 10-week-old obese / diabetic mice were used in each experimental group, and the experimental group was diluted with maize lignan in corn oil in a daily dosage of 10 mg / kg. Each dose was administered at a constant time for 10 days, and the control group received only the same amount of corn oil. At 10 days after the start of administration, blood glucose levels of the test and control groups were measured and analyzed.

After 10 days after oral administration, the blood glucose levels of the experimental group and the control group were measured, and the control group had significantly higher blood glucose (420.63 ± 10.66 mg / dl) compared with that of the mayis lignan group (317.23 ± 22.95 mg / dl). , p <0.01) The decrease in blood sugar level was observed, and the prevention and treatment effect of diabetes was observed.

<Manufacture example 1>

Preparation of a medicament containing the pharmaceutical composition for treating or preventing diabetes mellitus according to the present invention

<1-1> Preparation of Tablet

25 mg of mayis lignan of the present invention was combined with 26 mg of lactose for excipients and 3.5 mg of Avicel (microcrystalline cellulose), 1.5 mg of sodium starch glyconate as a disintegration aid, and 8 mg of low-hydrosyprophylcellulose (L-HPC) for binders. The mixture was put in a U-type mixer and mixed for 20 minutes. After mixing was completed, 1 mg of magnesium stearate was further added as a lubricant and mixed for 3 minutes. Tablets were prepared by tableting and film coating after a quantitative test and a humidity test.

<1-2> Preparation of Syrup

A syrup containing maye lignan of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient of 2% (W / V) was prepared by the following method: 2 g of acid addition salt of maye lignan of the present invention, 0.8 g of saccharin, and 25.4 g of sugar was dissolved in 80 g of warm water. After cooling the solution, 8.0 g of glycerin, 0.04 g of flavor, 4.0 g of ethanol, 0.4 g of sorbic acid, and an appropriate amount of distilled water were mixed thereto. Water was added to the mixture to make 100 mL.

<1-3> Preparation of Capsule

A capsule was prepared by mixing 50 mg of macelignan of the present invention, 50 mg of lactose, 46.5 mg of starch, 1 mg of talc, and an appropriate amount of magnesium stearate and filling it into a hard gelatin capsule.

<1-4> Preparation of Injection Solution

Injectable solutions containing 10 mg of the active ingredient were prepared by the following method: 100 ml were prepared by dissolving 1 g of mayis lignan hydrochloride, 0.6 g of sodium chloride, and 0.1 g of ascorbic acid in distilled water. The solution was bottled and sterilized by heating at 20 ° C. for 30 minutes.

As described above, the mayis lignan of the present invention may act as a ligand of PPARγ, and may be useful as an insulin resistant type 2 diabetes prevention and treatment agent because it has a function of significantly reducing blood glucose in an obese / diabetic animal experimental model. .

Claims (3)

Ligand of the PPARγ receptor, characterized in that it contains mayis lignan represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient [Formula I]

A pharmaceutical composition for treating or preventing a disease in response to activation of the PPARγ receptor, using an effective amount of the mayis lignan of claim 1 or a pharmaceutically acceptable salt thereof The pharmaceutical composition of claim 2, wherein the disease responsive to activation of the PPARγ receptor is type 2 insulin resistant diabetes.

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