Composition for Preventing or Treating Obesity or Lipid-Related Metabolic Disorders

Abstract

The present disclosure relates to a functional composition for the prevention, amelioration or treatment of obesity or lipid-related metabolic disorders, which comprises a steroid sulfatase inhibitor as an active ingredient.

Claims

1-14. (canceled)

15. A method for preventing, ameliorating or treating obesity, comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising a steroid sulfatase inhibitor to a subject.

16. The method of claim 15, wherein the steroid sulfatase inhibitor is one or more selected from the group consisting of irosustat, 2-(hydroxyphenyl)indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate (E1-3-MTP), estrone-3-O-sulfamate (EMATE), 4-methylcoumarin 7-O-sulfamate (COUMATE), KW-2581, STX213, and morpholino.

17. The method of claim 15, wherein the pharmaceutical composition comprises a salt, hydrate or solvate form of the steroid sulfatase inhibitor.

18. A method for preventing, ameliorating or treating lipid-related metabolic disease, comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising a steroid sulfatase inhibitor to a subject.

19. The method of claim 18, wherein the steroid sulfatase inhibitor is one or more selected from the group consisting of irosustat, 2-(hydroxyphenyl)indole sulfate, 5-androstene-3,17-diol-3 sulfate, estrone-3-O-methylthiophosphonate, estrone-3-O-sulfamate, 4-methylcoumarin 7-O-sulfamate, KW-2581, STX213, and morpholino.

20. The method of claim 18, wherein the pharmaceutical composition comprises a salt, hydrate or solvate form of the steroid sulfatase inhibitor.

21. The method of claim 18 wherein the lipid-related metabolic disease is selected from the group consisting of diabetes, hyperlipidemia, hepatic steatosis, hepatitis, liver cirrhosis, arteriosclerosis, hypertension, cardiovascular disease, and metabolic syndromes in which the above diseases occur simultaneously.

Description

DESCRIPTION OF DRAWINGS

[0061] FIG. 1 graphically shows the results of measuring changes in mouse body weight after administering irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 1.

[0062] FIGS. 2a and 2b are X-ray images taken after administering irosustat (FIG. 2b) or a vehicle (FIG. 2a) to a high-fat-diet-induced obesity mouse model in Experimental Example 2.

[0063] FIG. 3 graphically shows the results of measuring changes in mouse fat mass and lean mass after administering irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 2.

[0064] FIGS. 4a and 4b shows microscopic images of mouse abdominal fat tissue, taken after administering irosustat (FIG. 4b) or a vehicle (FIG. 2a) to a high-fat-diet-induced obesity mouse model in Experimental Example 3.

[0065] FIG. 5 graphically shows the results of measuring the size of mouse adipocytes after administering irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 3.

[0066] FIGS. 6a and 6b shows microscopic images of mouse liver tissue, taken after administering irosustat (FIG. 6b) or a vehicle (FIG. 6a) to a high-fat-diet-induced obesity mouse model in Experimental Example 4.

[0067] FIG. 7 graphically shows the results of measuring changes in blood glucose level after performing a glucose tolerance test following administration of irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 5.

[0068] FIG. 8 graphically shows the results of measuring AUC (area under the glucose-time curve) after performing a glucose tolerance test following administration of irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 5.

[0069] FIG. 9 graphically shows the results of measuring changes in blood glucose level after performing an insulin tolerance test (ITT) following administration of irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 5.

[0070] FIG. 10 graphically shows the results of measuring AUC (area under the glucose-time curve) after performing an insulin tolerance test following administration of irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 5.

[0071] FIG. 11 graphically shows the results of measuring changes in blood cholesterol level after administering irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 6.

[0072] FIG. 12 graphically shows the results of measuring changes in blood triglyceride level after administering irosustat or a vehicle to a high-fat-diet-induced obesity mouse model in Experimental Example 6.

BEST MODE

[0073] One embodiment of the present disclosure is directed to a composition for the prevention, amelioration or treatment of obesity, the composition comprising a steroid sulfatase inhibitor as an active ingredient.

[0074] Another embodiment of the present disclosure is directed to a composition for the prevention, amelioration or treatment of lipid-related metabolic disease, the composition comprising a steroid sulfatase inhibitor as an active ingredient.

[0075] Still another embodiment of the present disclosure is directed to a method for the prevention or treatment of obesity, the method including administering a pharmaceutically effective amount of a steroid sulfatase inhibitor to a subject.

[0076] Yet another embodiment of the present disclosure is directed to a method for the prevention or treatment of lipid-related metabolic disease, the method including administering a pharmaceutically effective amount of a steroid sulfatase inhibitor to a subject.

MODE FOR INVENTION

[0077] Hereinafter, the present disclosure will be described in more detail with reference to examples. It will be obvious to those skilled in the art that these examples are merely to describe the present disclosure in more detail and the scope of the present disclosure according to the subject matter of the present disclosure is not limited by these examples.

EXAMPLES

Preparation Example 11 Preparation of Irosustat

[0078] The compound (6-oxo-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-3-yl) sulfamate (hereinafter referred to as “irosustat”) represented by the following Formula 1 was purchased and prepared:

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Experimental Example 11 Weight Loss Effect in High-Fat-Diet-Induced Obesity Mouse Model

[0079] 8-week-old C57BL/6 mice were fed with a 60% high-fat diet, and a vehicle or irosustat (10 mg/kg) prepared in Preparation Example 1 was administered orally to the mice once a day for a total of 10 days. The body weights of the mice were measured at the same time every week, and the results are graphically shown in FIG. 1.

[0080] As shown in FIG. 1, it could be confirmed that the body weight of the control group to which the vehicle was administered was 36.4+/−3.4 g, whereas the body weight of the drug-administered group to which irosustat was administered was 31.4+/−5.0 g, suggesting that the body weight of the drug-administered group significantly decreased by about 14% compared to that of the control group.

Experimental Example 21 Fat Reduction Effect (1) in High-Fat-Diet-Induced

Obesity Mouse Model

[0081] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the mice were imaged using DEXA (Dual-energy X-ray absorptiometry) after the vehicle or irosustat was administered orally to the mice for 13 weeks. The images are shown in FIGS. 2a and 2b. In addition, the fat masses and lean masses of the mice were measured, and the results are shown in FIG. 3.

[0082] As shown in FIGS. 2a, 2b and 3, the fat mass of the drug-administered group to which irosustat was administered significantly decreased compared to that of the control group to which the vehicle was administered, but the body weight except fat, that is, lean mass, was similar between the two groups, suggesting that the mouse weight loss effect in Experimental Example 1 is attributable to fat reduction.

Experimental Example 31 Fat Reduction Effect (2) in High-Fat-Diet-Induced Obesity Mouse Model

[0083] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the mice were euthanized after oral administration of irosustat for 13 weeks and abdominal fat tissue was taken and then imaged with a microscope. The images are shown in FIGS. 4a and 4b. In addition, the areas of adipocytes in the abdominal fat tissue in the control group and the drug-administered group were measured, and the results are shown in FIG. 5.

[0084] As shown in FIGS. 4a, 4b and 5, it could be confirmed that the size of adipocytes in the drug-administered group to which irosustat was administered significantly decreased compared to that in the control group to which the vehicle was administered.

Experimental Example 41 Hepatic Steatosis Amelioration Effect in High-Fat-Diet-Induced Obesity Mouse Model

[0085] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the mice were euthanized after oral administration of irosustat for 13 weeks and hepatic tissue was taken and then imaged with a microscope. The images are shown in FIGS. 6a and 6b.

[0086] As shown in FIGS. 6a and 6b, it could be confirmed that the findings of hepatic steatosis caused by the high-fat diet in the drug-administered group to which irosustat was administered were significantly improved compared to those in the control group to which the vehicle was administered.

Example 5 Increase in Glucose/Insulin Sensitivity in High-Fat-Diet-Induced Obesity Mouse Model

[0087] 1. Glucose Tolerance Test (GTT)

[0088] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the mice were fasted for 16 hours after oral administration of irosustat for 11 weeks, and glucose was injected intraperitoneally into the mice at a dose of 1 g/kg body weight. 0 min, 15 min, 30 min, 60 min, 90 min and 120 min after intraperitoneal injection, blood was collected from the tail of each mice and the glucose level in the blood was measured. The results are shown in FIG. 7. However, during the glucose tolerance test, a stable environment was provided to the experimental animals. In addition, AUC (area under the glucose-time curve) was measured using the following Equation 1 and the results are shown in FIG. 8. In Equation 1, C0, C15, C30, C60, C90 and C120 are glucose levels measured at 0 min, 15 min, 30 min, 60 min, 90 min and 120 min, respectively.

AUC=0.5×(0.5×C0+C15+C30+C60+C90+0.5×C120)  [Equation 1]

[0089] As shown in FIGS. 7 and 8, the blood glucose level in the drug-administered group to which irosustat was administered significantly decreased compared to that in the control group to which the vehicle was administered.

[0090] 2. Insulin Tolerance Test (ITT)

[0091] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the mice were fasted for 2 hours after oral administration of irosustat for 12 weeks, and then the blood glucose levels of the mice were measured and insulin was injected intraperitoneally into the mice at a dose of 0.8 units/kg body weight. 0 min, 15 min, 30 min, 60 min, 90 min and 120 min after intraperitoneal injection, blood was collected from the tail of each mice and the glucose level in the blood was measured. The results are shown in FIG. 9. In addition, AUC was measured using Equation 1 above and the results are shown in FIG. 10.

[0092] As shown in FIGS. 9 and 10, it could be confirmed that the blood glucose level in the drug-administered group to which irosustat was administered significantly decreased compared to that in the control group to which the vehicle was administered.

Experimental Example 61 Decreases in Blood Cholesterol and Triglyceride Levels in High-Fat-Diet-Induced Obesity Mouse Model

[0093] An experiment was performed under the same conditions as in Experimental Example 1 above, except that the blood cholesterol and triglyceride levels in the control group and the drug-administered group were measured after oral administration of irosustat for 13 weeks. The results of measurement of the cholesterol and triglyceride levels are shown in FIGS. 11 and 12, respectively.

[0094] As shown in FIGS. 11 and 12, it could be confirmed that the blood cholesterol and triglyceride levels in the drug-administered group to which irosustat was administered significantly decreased compared to those in the control group to which the vehicle was administered.

[0095] Although the present disclosure has been described in detail based on the above results, it will be obvious to those skilled in the art to which the present disclosure pertains that the scope of the present disclosure is not limited thereto and various modifications and alterations are possible, without departing from the technical spirit of the present disclosure as described in the appended claims.

INDUSTRIAL APPLICABILITY

[0096] The composition which is provided by the present disclosure may effectively prevent, ameliorate or treat obesity by lowering the body fat content and reducing the size of adipocytes. In addition, the composition which is provided by the present disclosure may also effectively prevent, ameliorate or treat lipid-related metabolic disease by ameliorating hepatic steatosis, increasing glucose/insulin sensitivity and lowering blood cholesterol or triglyceride levels.