KR101311534B1 - A composition for treating or preventing diabetes comprising 4-hydroxy tamoxifen analog or pharmaceutically acceptable salts thereof as an effective ingredient - Google Patents

Abstract

The present invention relates to a composition for treating or preventing diabetes comprising GSK5182, a 4-hydroxy tamoxifen analog, as an active ingredient, and is a 4-hydroxy tamoxifen analog that can suppress glucose production gene expression and lower blood glucose levels. It relates to a composition for treating or preventing diabetes comprising GSK5182 as an active ingredient.

Description

A composition for treating or preventing diabetes comprising 4-hydroxy tamoxifen analog or pharmaceutically acceptable salts especially as an effective ingredient} A composition for treating or preventing diabetes comprising 4-hydroxy tamoxifen analog or a pharmaceutically acceptable salt thereof as an effective ingredient

The present invention comprises a 4-hydroxy tamoxifen analog or a pharmaceutically acceptable salt thereof as an active ingredient, a composition for treating or preventing diabetes, a method for treating or preventing diabetes using the composition, and a 4-hydroxy tamoxifen analog It relates to a food composition for preventing or improving diabetes.

Diabetes mellitus is a disease in which carbohydrate metabolism occurs due to lack of insulin or lack of insulin sensitivity.

Insulin, a polypeptide hormone, is made from beta cells in the island of Langerhans in the pancreas, and most cells in the body are required for the use of glucose, or glucose. In diabetics, excess sugar is excreted in the urine as the body's ability to use glucose normally impairs blood glucose levels and builds up more and more glucose in the blood.

There are two types of diabetes. Type I is insulin-dependent diabetes mellitus (IDDM), formerly known as juvenile diabetes, requiring insulin injections. This is because insulin is not secreted from the pancreas, so insulin must be supplied by injection. Type II is a type of non-insulin-dependent diabetes mellitus (NIDDM) called adult-type diabetes mellitus, which can be controlled by diet. It is caused by poor insulin secretion of the pancreas or tissue rejection of insulin, which is exacerbated by subtle changes in beta cells secreting insulin. The two types of diabetes were previously classified as juvenile diabetes and adult diabetes, but both can occur at any age. However, insulin-independent diabetes is much more common, accounting for 90% of all diabetics.

As described above, most insulin injections are used to treat insulin-dependent diabetes, namely type 1 (type I) diabetes.

Meanwhile, many substances have been researched and developed for treating conventional insulin-independent diabetes, that is, type 2 (type II) diabetes. Specifically, PPAR- [gamma] activators, GLP-1 derivatives, DPP-IV inhibitors, PTP1B inhibitors, and the like are the major diabetes therapeutics that have been developed. PPAR- [gamma] activators are known to be effective for diabetes by increasing insulin sensitivity, and specific examples thereof include thiazolidinedione. On the other hand, GLP-1 derivative is a powerful incretin hormone secreted by the intestine, which promotes the secretion of insulin in the body, activates beta cells, restores insulin sensitivity, and intestinal exercise without side effects of hypoglycemia. It is known to be effective for diabetes by controlling food intake by reducing food intake. In addition, DPP-IV inhibitors are produced in the gastrointestinal post-prandial diet and selectively inhibit DPP-IV enzymes, which directly degrade the incretin enzymes that promote insulin secretion and lower blood sugar levels, thereby maintaining high levels of incretin enzymes for a long time. It is known to be effective for diabetes. The most recent drug target is PTP1B. Mice with PTP1B removal showed improved glucose metabolism, decreased insulin levels and resistance to weight gain. Efficient and specific PTP1B inhibitors are under development, and antisense-inhibited PTP1B expression has been shown to show good results in animal experiments.

However, these conventional drugs show side effects due to their respective mechanisms. For example, the symptoms of weight gain along with toxicity to the liver, kidneys, muscles and heart are typical side effects. Therefore, there is an urgent need for the development of a diabetes treatment agent capable of treating or preventing diabetes at the same time while having fewer side effects and causing weight gain.

In view of the above, the present inventors are looking for an effective substance for diabetes, and the 4-hydroxy tamoxifen analog, GSK5182, may inhibit the expression of the gene for producing glucose and lower the level of glucose in the blood, which may be effective in treating diabetes. This confirmation completed the present invention.

It is an object of the present invention to provide a pharmaceutical composition for treating or preventing diabetes, comprising 4-hydroxy tamoxifen analog or a pharmaceutically acceptable salt thereof as an active ingredient.

It is another object of the present invention to provide a food composition for preventing or ameliorating diabetes comprising 4-hydroxy tamoxifen analog or a food acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for treating diabetes by administering the pharmaceutical composition for treating or preventing diabetes.

In one embodiment, the present invention provides a composition for treating or preventing diabetes, comprising 4-hydroxy tamoxifen analog of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the 4-hydroxy tamoxifen analog is (Z) -4- (1- {4- [2- (dimethylamino) ethoxy] phenyl} -5-hydroxy-2-phenylpent-1-enyl ) Phenol [(Z) -4- (1- {4- [2- (dimethylamino) ethoxy] phenyl} -5-hydroxy-2-phenylpent-1-enyl) phenol]. The compound of Formula 1 is also called GSK5182. Although GSK5182 is known as an inhibitor of ERRγ (estrogen-related receptor gamma), it has not been disclosed for the purpose of treating a disease, and the inventors have found that there is a use for treating diabetes for the first time.

In the present invention, GSK5182 may be synthesized by a known synthesis method, or may be commercially available.

In the present invention, GSK5182 may be prepared with pharmaceutically or food acceptable salts and solvates according to methods conventional in the art.

As pharmaceutically or food acceptable salts, acid addition salts formed by free acid are useful. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, and trifluoro may be used as the organic acid. Acetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, Galacturonic acid, glutamic acid, glutaric acid (glutaric acid), glucuronic acid (glucuronic acid), aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used.

Bases may also be used to prepare pharmaceutically or food acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. As the metal salt, it is particularly preferable to produce sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The composition comprising GSK5182 of the present invention is characterized by reducing glucose levels in the liver to prevent or treat diabetes, and also prevent or treat diabetes by reducing glucose levels in blood.

In the present invention, the term "diabetes" refers to a disease that occurs when insulin secretion is insufficient or when insulin does not sufficiently function and function, and when this disease occurs, glucose in the liver or blood due to excessive decomposition of glycogen, protein and fat An abnormal increase in concentration causes diabetes and ketoneuria, resulting in pathological conditions such as circulatory disorders and kidney disorders along with blood concentration due to electrolyte loss due to abnormality of water and electrolyte metabolism. Insulin is secreted from the beta cells of the island of Langerhans in the pancreas, secreted when blood glucose concentration increases, and when decreased, secretion is inhibited to regulate proper activity of energy sources. The disease is divided into insulin dependent diabetes mellitus (type I) and insulin independent diabetes mellitus (type II). Diagnosis of diabetes is generally possible through measurement of blood glucose levels, which differ according to criteria. In humans, diabetes is usually diagnosed when glucose in the blood is at least 200 mg / dl and fasting at 140 mg / dl. Therefore, lowering the glucose concentration in the blood or in the liver can treat or prevent diabetes.

The term "prevention" in the present invention refers to any action that inhibits or delays the development of diabetes by administration of the composition according to the present invention.

As used herein, the term "treatment" refers to any action by which administration of a composition according to the invention improves or advantageously alters the symptoms of the disease.

In one embodiment of the present invention, it was confirmed that GSK5182 inhibits the expression of the gene for producing glucose and lowers the glucose level in the blood or liver, thereby having an effect in treating diabetes.

In particular, in one embodiment of the present invention, the results of experiments to confirm the role of GSK5182 in the regulation of glucose production, it was confirmed that the strong suppression of pyruvate-dependent induction of glucose levels in the blood compared to the control (Fig. 4). In addition, the anti-diabetic effects and toxicity of GSK5182 and metformin, a second diabetes treatment, were compared in mice. It was confirmed that GSK5182 recovered normal blood glucose within the normal fasting glucose level, and that GSK5182 was caused by the diabetes phenotype. It was confirmed that a significant improvement compared to metformin with respect to liver toxicity (Figs. 5- 6, and 7a-7b).

In a preferred embodiment of the present invention, the composition of the present invention is a pharmaceutical composition.

When the composition of the present invention is a pharmaceutical composition, the composition may include a pharmaceutically acceptable carrier. The composition comprising a pharmaceutically acceptable carrier can be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups. In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.

The pharmaceutical composition may be in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories It can have one formulation.

The composition of the present invention is administered in a pharmaceutically effective amount.

As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to the individual type and severity, age, sex, type of virus infected. , The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the drug used concurrently, and other factors well known in the medical field. However, for the desired effect, the 4-hydroxy tamoxifen analog of Formula 1 or a salt thereof is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 10 mg / kg.

The antidiabetic or therapeutic agent of the present invention may be administered daily or intermittently, and the number of administrations per day may be administered once or divided into two or three times. The frequency of administration in the case where the two active ingredients are single drugs may be the same or different times. In addition, the composition of the present invention can be used alone or in combination with other drug treatments for the prevention or treatment of diabetes diseases. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

In a preferred embodiment of the present invention, the composition of the present invention is a food composition.

That is, GSK5182 or a salt thereof may be added to the food composition for the purpose of preventing or ameliorating diabetes. When GSK5182 or its salt is used as a food additive, GSK5182 or its salt can be added as it is or used with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). In general, GSK5182 or a salt thereof is added in the amount of 0.0001 to 1% by weight, preferably 0.001 to 0.1% by weight in the raw material composition in the manufacture of food or beverage. However, in the case of long-term ingestion intended for health and hygiene purposes or for the purpose of controlling health, the amount can also be used in the above-mentioned range.

There is no particular limitation on the kind of the food. Examples of the food to which the above substances can be added include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, A carbonating agent used in a carbonated beverage, and the like. The proportion of such additives is not critical, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention. In addition, the composition of the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. The proportion of such flesh is not critical but is generally selected in the range of 0.01 to 10 parts by weight per 100 parts by weight of the composition of the present invention. These components can be used independently or in combination.

In another aspect, the present invention provides a method for treating diabetes comprising administering an effective amount of a 4-hydroxy tamoxifen analog, represented by Formula 1, or a pharmaceutically acceptable salt thereof, to a subject having or possibly developing diabetes. To provide. The diabetes includes type 1 diabetes and type 2 diabetes.

As used herein, the term "individual" means all animals, including humans, who have already developed or can develop diabetes, and can effectively prevent and treat such diseases by administering to a subject a composition comprising GSK5182 or a salt thereof.

The optimal amount and dosage interval of the individual doses of the compounds of the present invention will be determined by the nature and extent of the disease being treated, the dosage form, the route and site, and the age and health of the particular patient being treated, which will ultimately be used by the physician. It will be appreciated by those skilled in the art that the appropriate dosage will be determined. Such dosing can be repeated as often as appropriate. If side effects occur, the dosage and frequency can be altered or reduced in accordance with normal clinical practice.

The route of administration of the composition may be administered via any conventional route so long as it can reach the target tissue. The composition of the present invention may be administered as intraperitoneal administration, intravenous administration, subcutaneous administration, intradermal administration, oral administration, but is not limited thereto. The composition may also be administered by any device capable of transferring the active agent to the target cell.

The present invention is to treat the diabetes mellitus comprising a 4-hydroxy tamoxifen analog GSK5182 as an active ingredient by confirming that GSK5182, a 4-hydroxy tamoxifen analog, inhibits the production of glucose genes, and is effective in treating diabetes by lowering glucose levels in the blood. There is an effect that can provide a prophylactic composition. It may also be applied to food compositions for preventing or ameliorating diabetes.

1 shows that GSK5182 (40 mg / kg / day) is administered intraperitoneally to db / db mice ( n = 6) for 5 days, followed by measurement of glucose in blood after 4 hours of fasting in vivo in blood. It is confirmed that the glucose level can be lowered.
2 is a graph showing that GSK5182 (40 mg / kg / day) was administered intraperitoneally to db / db mice ( n = 6) for 5 days, and then GSK5182 treatment significantly reduced glucose production gene expression in liver. . At this time, Q-PCR was performed using total RNA isolated from liver of db / db mice.
FIG. 3 shows PEPCK in liver of db / db mice administered GSK5182 (40 mg / kg / day) intraperitoneally to db / db mice ( n = 6) for 5 days. Of promoter ChIP analysis showing the occupancy of PGC-1α on ERRE.
4 is a graph showing that GSK5182 inhibits glucose production for pyruvate challenge. DIO mice fasted for 17 hours (n = 5) were challenged with pyruvate at 1 g / kg after vehicle or GSK5182 (40 mg / kg).
5 is a graph showing the anti-diabetic effect of GSK5182 and metformin in db / db mice ( n = 5). The antidiabetic effect was determined after fasting for 4 hours in db / db mice administered with vehicle, GSK5182 (40 mg / kg / day) or metformin (40 mg / kg / day) for 21 days.
FIG. 6 shows Q-PCR analysis of glucose producing gene expression using liver RNA of db / db mice administered GSK5182 (40 mg / kg / day) or metformin (40 mg / kg / day) intraperitoneally for 21 days.
FIG. 7 shows the results of measuring db / db mouse blood glucose levels and body weight before administration of GSK5182 (40 mg / kg / day) or metformin (40 mg / kg / day) intraperitoneally for 21 days. At this time, blood glucose level (a) and body weight (b) were measured under ad libitum 1 day before administration of GSK5182 or metformin.
8 is a graph showing the effect on dietary intake (a) and body weight (b) following administration of GSK5182 (40 mg / kg / day) or metformin (40 mg / kg / day) intraperitoneally for 21 days. Dietary intake and body weight were measured for 21 days.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Materials and methods

Example  1: Preparation of Compound

Insulin, 8-bromoadenosine 3 ', 5'-cyclic monophosphate (8-Br-cAMP) and dexamethasone were purchased from Sigma and used in the recommended solvents.

GSK5182 was used in HCl salt form, in vivo For the experiment It was dissolved in a sterile filtered 30% PEG-400 aqueous solution and prepared and used at a concentration of 40 mg / kg. In addition, metformin (metformin), which is widely used as a therapeutic agent for diabetes, was used for comparison and analysis of anti-diabetic and detoxification efficacy, etc. from Sigma.

Example  2: Chromatin Immune sedimentation ( ChIP ) analysis

Nuclear isolation and crosslinking on liver samples was performed as previously known (Dufour CR et al. Cell Metab , 2007, 5, p. 345-356; Lee YS et al. Biochem J , 2008, 413, p. 559-569). After sonication, soluble chromatin was added for immunoprecipitation with anti-PGC-1α (Santa Cruz). DNA was recovered with phenol / chloroform extract and analyzed by PCR or Q-PCR using primers for the corresponding promoter.

Example  3: Animal experiment

Animal experiments were performed for 12 hours by introducing 7-week-old male db / db mice widely used as diabetic model animals and 8-week-old male C57BL / 6 mice used as dietary-induced obesity model animals (DIO) from Charles River laboratories. Experiments were conducted to ensure that feed was sufficiently maintained in light / dark cycles. First, experiments using db / db mice were assigned n = 6 animals per group to observe the anti-diabetic effect of short-term GSK5182 administration. GSK5182 (40 mg / kg / day) was used in the experimental group and vehicle was used in the control group. Glucose levels in blood fasted for 4 hours on days 2, 3, 4 and 5 with dosing for days were measured. In addition, to determine the sustained anti-diabetic efficacy by long-term administration of GSK5182, five db / db mice were assigned per group, GSK5182 (40 mg / kg / day), widely used as a diabetes treatment and metformin (40 mg / kg / day). In the control group, blood glucose and body weight were measured at two-day intervals while the vehicle was administered intraperitoneally for three weeks (21 days). After the GSK5182 and metformin treated 21 days was collected and plasma at the expense of db / db mice for toxicity related to efficacy analysis of such tissues or organs of the db / db mouse, GOT, GPT, BUN, blood, such as CRE and CK Chemical indicators were measured using an automatic blood chemistry analyzer (Hitachi 7150, Japan). On the other hand, animal experiments for the inhibition of glucose production in the liver for the pyruvate challenge, 8-week-old male C57BL / 6 mice assigned to each group n = 5 for a high-fat diet (60 kcal% fat, D12492, Research Diets) to obtain a diet-induced obesity (DIO) model, fasted for 17 hours, then challenged with 1 g / kg pyruvate after administration of GSK4182 (40 mg / kg), 30, Blood glucose concentrations were measured at 60, 90, 120, 150 and 180 minutes.

Example  4: quantitative PCR

Quantitative For PCR Total RNA from the liver of db / db mice was extracted using RNeasy mini-kit (Qiagen). Then cDNA was made using Superscript II enzyme (Invitrogen) and analyzed by Q-PCR using SYBR green PCR kit and TP800, Thermal Cycler DICE Real Time system (TAKARA). All data were normalized to ribosomal L32 expression.

Example  5: statistical analysis

All values are expressed as mean ± standard error (SEM). The significance between the mean values was assessed by two-tailed unpaired students t- test.

result

Experimental Example  One: In vivo In the model GSK5182 Of hypoglycemic effect and hepatic glucose suppression

GSK5182 is in db / db as an in vivo diabetic animal model Glucose levels in fasting blood of mice treated with and without GSK5182 were measured by intraperitoneal administration to mice for 5 days. Indeed, GSK5182-administered mice showed a significant decrease in glucose levels in fasting blood as compared to the control group (FIG. 1). In addition, GSK5182 was expressed in glucose producing genes (FIG. 2) and in db / db mice. The occupancy of PGC-1α on PEPCK ERREs (FIG. 3) was significantly reduced.

In addition, to identify the role of GSK5182 in the regulation of hepatic glucose production, we used a diet-induced obesity (DIO) model to determine the level of glucose in the blood in response to administration of pyruvate, a precursor for glucose production. A pyruvate challenge test was performed to monitor the change. As expected, GSK5182 strongly inhibited pyruvate-dependent induction of glucose levels in the blood compared to the control group (FIG. 4).

Experimental Example  2: GSK5182 Of anti-diabetic effect and toxicity

In order to directly evaluate and compare the anti-diabetic effects and toxicity of GSK5182 with the standard anti-diabetic drug metformin, we db / db mice were administered intraperitoneally with GSK5182 or metformin for 21 days. The degree of glucose and glucose producing gene inhibition in blood by GSK5182 was compared with that by metformin (FIGS. 5-6, and 7A-7B). The results are shown in Table 1 below. Surprisingly, the treatment of GSK5182 almost restored normal blood glucose levels in db / db mice (110 vs. 241 mg / dl) (glucose in fasting blood at 110 mg / dl was normal fasting glucose levels in humans (72-126 mg / dl). ) Within range). On the other hand, although 21-day treatment of metformin significantly reduced blood glucose levels (154 vs. 241 mg / dl), glucose levels did not reach normal physiological ranges. In addition, hepatotoxicity caused by the expression of the diabetic phenotype in db / db mice was significantly improved upon GSK5182 treatment, but not on metformin treatment, as evidenced by the GOT and GPT tests. Indeed, GSK5182 treatment restored plasma GPT levels to the normal physiological range (between 9-60 IU / L) and significantly reduced plasma GOT levels. The dose of GSK5182 or metformin used in the present invention showed no signs of kidney, muscle and cardiac toxicity.

GOT
(IU / L)
(9-60) GPT
(IU / L)
(5-40) BUN
(mg / dl)
(> 60) CRE
(mg / dl)
(0.6-1.2) CK
(U / L)
(60-400) GLU
(mg / dl)
(72-126) Control group
(Vehicle) 123 ± 10 90 ± 11 24.8 ± 1.3 0.48 + 0.02 950 ± 171 241 ± 27 Metformin
(40 mg / kg) 118 ± 18 117 ± 27 18 ± 1.1 ^* 0.36 ± 0.03 ^* 1323 ± 729 154 ± 17 GSK5182
(40 mg / kg) 83 ± 4 ^** 41 ± 2 ^** 20.4 ± 1.3 0.37 ± 0.02 ^** 405 ± 114 ^* 110 ± 6.5 ^* GOT: glutamic-oxaloacetic transaminase
GPT: glucamic-pyruvic transaminase
BUN: blood urea nitrogen
CRE: creatinine
CK: creatin kinase
GLU: blood glucose
(): normal physiological range
* P <0.05, ** P <0.01 by two-tailed Student t -test
Data are reported as mean ± standard error.

On the other hand, GSK5182 treatment did not show any significant changes in food intake and body weight (Figs. 8a and 8b).

Overall, these results suggest that GSK5182 improves the hyperglycemic phenotype by regulating liver glucose production in type 2 diabetic mice.

In addition, GSK5182 not only can cure diabetes, but suggests that such GSK5182 is not toxic and there are no in vivo side effects of ingestion.

Claims (6)

A pharmaceutical composition for treating or preventing diabetes, comprising 4-hydroxy tamoxifen analog of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and showing no hepatotoxicity while reducing glucose levels in liver and blood.
[Formula 1]

According to claim 1, wherein the pharmaceutical composition is a pharmaceutical composition for treating or preventing diabetes, further comprising a pharmaceutically acceptable carrier. The pharmaceutical composition for treating or preventing diabetes of claim 1, wherein the pharmaceutical composition has a plasma GPT level and a GOT level of 40 ± 5 (IU / L) and 80 ± 10 (IU / L), respectively, after administration. . The pharmaceutical composition for treating or preventing diabetes of claim 1, wherein the pharmaceutical composition reduces glucose levels in blood to 72-126 mg / dl. A 4-hydroxy tamoxifen analog of Formula 1 or a food-acceptable salt thereof as an active ingredient, a food composition for preventing or improving diabetes, which does not show hepatotoxicity while reducing glucose levels in liver and blood.
[Formula 1]

The food composition of claim 5, wherein the food composition further comprises a food acceptable carrier.

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