WO2008075741A1

WO2008075741A1 - Therapeutic agent and prophylactic agent for diabetes

Info

Publication number: WO2008075741A1
Application number: PCT/JP2007/074553
Authority: WO
Inventors: Midori Awazu; Michiaki Kohno
Original assignee: Keio University; Nagasaki University
Priority date: 2006-12-20
Filing date: 2007-12-20
Publication date: 2008-06-26
Also published as: JPWO2008075741A1

Abstract

Disclosed is a novel pharmaceutical agent which is effective for the treatment of type-2 diabetes, the treatment of borderline diabetes and the prevention of diabetes. A pharmaceutical agent comprising an MEK inhibitor as an active ingredient can be used as a therapeutic agent for type-2 diabetes, a therapeutic agent for borderline diabetes, an ameliorating agent for impaired glucose tolerance, an ameliorating agent for impaired fasting glucose, an anti-hyperglycemic agent, and a prophylactic agent for diabetes. The MEK inhibitor is not particularly limited, as long as it comprises a compound capable of inhibiting the function of MEK in the Ras/Raf/MEK/ERK pathway. Examples of the compound capable of inhibiting the function of MEK include PD184352, PD98059, U0126, PD0325901, ARRY-142886 and ARRY-438162, and PD184352 or PD0325901 is particularly preferred. These compounds may be synthesized by techniques known to those skilled in the art, or may be commercially available products. The above-mentioned agents may be orally administered.

Description

Specification

Diabetes treatment and prevention agent

Technical field

[0001] The present invention relates to a therapeutic agent and a preventive agent for diabetes.

Background art

[0002] In recent years, the number of patients with diabetes in Japan, particularly type 2 diabetes (non-insulin dependent diabetes mellitus; MDDM), which is a non-insulin-dependent condition, has been increasing. This increase in the number of type 2 diabetes patients is thought to be due to changes in lifestyle habits such as obesity and lack of exercise due to increased fat intake.

[0003] If the long-lasting hyperglycemia characteristic of diabetes is left untreated for a long period of time, a specific complication occurs and the quality of life of the patient is reduced. Therefore, diabetes needs to be treated early to bring blood sugar levels close to normal and prevent the development of complications. Treatment methods for diabetes include diet therapy, exercise therapy, and pharmacotherapy. If blood glucose levels are not improved by diet therapy or exercise therapy, insulin therapy, sulfonylurea drugs, sulfonamide drugs, Drugs such as biguanides, a-darcosidase inhibitors, thiazolidine drugs, and rapid-acting insulin secretagogues (Powers AC: Diabetes mellitus: Long-term treat ment. In: Harrison's Principles of Internal Medicine. 16th Ed Eds, asper, Braunwa Id, Fauci, Hansen, Longo, Jameson. New York, McGraw-Hill, 2005, pp2170-2178) ₀ Developed anti-diabetic drugs with new mechanisms of action, as they may not be effective, postprandial blood glucose levels may be insufficiently controlled, or these drugs may not be administered due to complications need to do A.

Disclosure of the invention

Problems to be solved by the invention

[0004] An object of the present invention is to provide a novel drug effective for type 2 diabetes treatment, borderline type diabetes treatment, and diabetes prevention. Means for solving the problem

[0005] ME (MAP / ER kinase) is a phosphorylase that activates ERK (MAP kinase) in the ERK-MAP kinase signal transduction pathway (Ras / Raf / ME K / ERK pathway). The ER K-MAP kinase signaling pathway is known to be involved in cell proliferation, and ME K inhibitors block the signal transduction system and suppress cell proliferation, thus treating cancer. It is considered that it is a useful drug (see Japanese Unexamined Patent Publication No. 2001-55376 and Japanese Unexamined Patent Publication No. 2000-212141).

[0006] However, as shown in the following examples, the present inventors have found that PD 184352 (CI_1040) and PD0325901, which are one of MEK inhibitors, are type 2 completely different from cell proliferative diseases. It was clarified that blood glucose levels were reduced as needed in diabetic model mice, and fasting blood glucose levels and glucose tolerance test results were improved in borderline diabetic model mice. From these results, the present inventors have clarified that administration of a MEK inhibitor improves the symptoms of diabetes, and have completed the present invention.

That is, the type 2 diabetes therapeutic agent, borderline type diabetes therapeutic agent, glucose tolerance abnormality improving agent, or fasting blood glucose level abnormality improving agent according to the present invention contains a MEK inhibitor as an active ingredient.

[0008] The hypoglycemic agent according to the present invention contains a MEK inhibitor as an active ingredient. The hypoglycemic agent is characterized by lowering blood glucose levels in patients who have abnormal blood glucose levels at any time. Moreover, the hypoglycemic agent is characterized by lowering postprandial blood glucose levels in patients with borderline diabetes. Furthermore, the hypoglycemic agent is characterized by lowering fasting blood glucose levels in borderline diabetic patients.

[0009] Further, the preventive agent for type 2 diabetes or borderline diabetes according to the present invention contains a MEK inhibitor as an active ingredient. The prophylactic agent prevents the onset of type 2 diabetes in patients with borderline diabetes.

[0010] Further, the oral preparation according to the present invention is used for the treatment of type 2 diabetes, the treatment of borderline diabetes, the improvement of glucose tolerance abnormality, the improvement of abnormal fasting blood glucose level, the reduction of blood glucose level, or the treatment of type 2 diabetes or borderline diabetes. An oral preparation for prevention, characterized by containing a MEK inhibitor as an active ingredient. [0011] Furthermore, the method for treating type 2 diabetes, the method for treating type 2 diabetes, the method for improving glucose tolerance abnormality, the method for improving fasting blood glucose level abnormality, or the method for lowering blood glucose according to the present invention are applied to humans or non-human vertebrates. On the other hand, the type 2 diabetes therapeutic agent, the borderline type diabetes therapeutic agent, the glucose tolerance improving agent, the fasting blood glucose level improving agent, or the hypoglycemic agent are administered to the vertebrate, respectively. .

[0012] Further, the method for preventing type 2 diabetes or borderline diabetes according to the present invention is a method for preventing type 2 diabetes or borderline diabetes in a human or a non-human vertebrate, the type 2 diabetes or A preventive agent for borderline diabetes is administered to the vertebrate.

[0013] Here, any of the above MEK inhibitors is preferably PD184352 or PD0325901. Any of the above drugs may be administered orally.

[0014] ——Cross-reference with related literature——

This application claims the benefit of the priority right of Japanese Patent Application No. 2006-343310 filed on December 20, 2006, and is incorporated herein by reference.

Brief Description of Drawings

[0015] [Fig. 1] (A) This is a diagram showing the judgment categories of the 75 g trans glucose tolerance test by the Japan Diabetes Society (1999). (B) 75g by the American Diabetes Society (The expert Committee on the Diagnosis and Classification of Diabetes Mullitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Ciabetes Care; 20, 1183-1197 (1997)) It is a figure which shows the determination division of the trans-glucose tolerance test.

FIG. 2 is a diagram showing the structural formulas of compounds used as MEK inhibitors and Ra loading agents. BEST MODE FOR CARRYING OUT THE INVENTION

[0016] Hereinafter, in the embodiment of the present invention, the power to be described specifically and in detail with reference to examples, the present invention is not limited to these.

[0017] When using commercially available reagent kits and measuring devices, unless otherwise explained, use the protocols attached to them.

[0018] The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification. Invention Can be reproduced. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention, and are shown for illustration or explanation. It is not limited to. It will be apparent to those skilled in the art that various modifications can be made based on the description of the specification within the intent and scope of the invention disclosed herein.

[0019] (1) Pharmacological action

In Japan, human diabetes was diagnosed based on the criteria (diabetes mellitus, 42, 385-404 (1999)) published in 1999 by the Committee on Diagnosis of Diabetes of the Diabetes Society of Japan. ing.

[table 1]

75gOGTT: 75g trans glucose tolerance test

[0020] As shown in Table 1, the Japan Diabetes Society has determined the human diabetes.

(i) Fasting blood glucose level Sl26mg / dl or more

(ii) 75g oral glucose tolerance test (75gOGTT) 2 hour value ¾00mg / dl or more

(iii) Blood glucose level over 200 mg / dl

Is defined as “diabetes” if it is confirmed by two or more tests performed on different days. Moreover, even if the blood glucose level is normal at any time, it is defined as “boundary type” if glucose glucose load is 110 mg / dl or more or 75 gOGTT 2-hour value Sl40 mg / dl or more at 75 gOGTT. 1 See (A)).

[0021] On the other hand, according to reports by the American Diabetes Society and WHO, when the fasting blood glucose level is 110-125 mg / dl and the 75 gOGTT 2-hour value is 140 mg / dl or less, "Impaired fasting glycemia (IFG)" and 75gOGTT 2 hour value Sl40 ～ 199mg / dl In this case, it is defined as “impaired glucose tolerance (IGT)” (see Figure 1 (B)).

[0022] The present inventors have shown that MEK inhibitors can improve various symptoms of diabetes using model mice that exhibit the same symptoms as those of diabetes. First, C57BL / KsJ-db / db mice (hereinafter referred to as “Type 2 diabetes model mice”) as “diabetic type” mice exhibiting insulin resistance (Chen, H, Charlat 0, Tartaglia LA, Woolf EA, Weng) X, Ellis SJ, Lakey ND, Culpepper J, Moore J, Breitbart RE, Duyk GM, Tepper RI, and Morganstern JP. Bvidence that the diabetes gene encodes the leptin receptor: identific ation of a mutation in the leptin receptor gene in db / db mice. Cell 84: 491-495, 199 6), after administration of MEK inhibitor, blood glucose level and insulin level were measured at any time. It was clarified that secretory insulin secretion is suppressed. In addition, when a glucose tolerance test was performed after administering a MEK inhibitor using a type 2 diabetes model mouse, it was also revealed that the blood glucose level after 2 hours of the glucose tolerance test decreased to near the normal level.

[0023] Furthermore, the inventors of the present invention are high-Fat as “border-type diabetes” model mice in which blood glucose levels are normal at any time, and blood glucose levels after 2 hours of fasting blood glucose and glucose load tests are abnormally high. Diet mouse (hereinafter referred to as “border-type diabetes model mouse”) (Winzell MS, Ahren B: The high-rat diet-fed mouse: a model for studying mechanisms and treatment or imp aired glucose tolerance and type 2 diabetes. Diabetes. 2004 Dec; 53 Suppl 3: S2l-9.) After administration of MEK inhibitor, glucose tolerance test was performed, and it was revealed that blood glucose level decreased to normal after 2 hours of glucose tolerance test did. Here, the “normal value” means the blood glucose level (approximately 120 to 180 mg / dl) of a healthy mouse that does not have a disease or the like! /.

[0024] Thus, the MEK inhibitor has an action of improving insulin resistance and lowering blood glucose level.

[0025] (2) Usefulness of drugs containing MEK inhibitors

(i) Type 2 diabetes therapeutic agent

In this way, by administering a sputum inhibitor to type 2 diabetes model mice, it is possible to reduce blood glucose levels to normal values at any time, while suppressing excessive insulin secretion, Fasting blood glucose level and glucose tolerance test 2 hour value can be decreased. Therefore, a drug containing a MEK inhibitor as an active ingredient has the effect of reducing blood glucose level, fasting blood glucose level, and postprandial blood glucose level at any time, and is useful for the treatment of type 2 diabetes. Here, the postprandial blood glucose level refers to a value measured approximately one and a half hours to two hours after the start of eating, and corresponds to a glucose tolerance test in mice for 1 to 2 hours.

[0026] In the treatment of type 2 diabetes, in addition to the administration of the drug of the present invention, other diabetic drugs (for example, insulin preparations, sulfonylureas, sulfonamides, biguanides, a-darcosidase inhibitors, Administration of drugs such as thiazolidine drugs and rapid-acting insulin secretagogues, diet therapy, exercise therapy, etc. may be combined.

[0027] (ii) Fasting glucose level abnormality improving agent and glucose tolerance abnormality improving agent

In addition, administration of MEK inhibitors to borderline diabetic mouse model mice can reduce the fasting blood glucose level and the glucose tolerance test 2-hour value to normal values. Therefore, a drug containing a MEK inhibitor as an active ingredient has the action of lowering fasting blood glucose level and postprandial blood glucose level, and treatment for improving fasting blood glucose level abnormality and glucose tolerance abnormality, that is, Useful for the treatment of borderline diabetes.

[0028] In addition to type 2 diabetes, diseases that cause impaired glucose tolerance include type 1 diabetes, Kashiwajima 0 gene function related to cell function, gene abnormality related to insulin action transmission mechanism, and vaginal exocrine secretion. There are diseases, endocrine diseases, liver diseases, exposure to drugs and chemicals, and infectious diseases. The drug containing the MEK inhibitor of the present invention as an active ingredient can be used for treatment for improving abnormal glucose tolerance caused by such diseases.

[0029] (iii) Hypoglycemic agent

From (i) and (ii) above, a drug containing a MEK inhibitor as an active ingredient can be used as a hypoglycemic agent in all situations. For example, a drug containing the MEK inhibitor of the present invention as an active ingredient decreases the blood glucose level, fasting blood glucose level, and postprandial blood glucose level of patients who have abnormal blood glucose levels in patients with type 2 diabetes. It is useful for lowering blood glucose level, fasting blood glucose level and postprandial blood glucose level in diabetic patients.

[0030] (iv) Diabetes preventive agent

From (iii) above, a drug containing a MEK inhibitor as an active ingredient reduces blood sugar straightness. Since it has an action, it is effective in preventing the onset of diabetes.

Specifically, if appropriate treatment is not performed for patients with borderline diabetes, insulin secretion failure and insulin resistance due to chronic hyperglycemia (glycotoxicity) will worsen, and type 2 diabetes will develop. It has been. Therefore, in order to prevent the onset of type 2 diabetes mellitus due to hyperinsulinemia (it is thought to be important to suppress cell fatigue from an early stage and to suppress postprandial blood glucose levels. Thus, a drug containing the MEK inhibitor of the present invention as an active ingredient can reduce fasting blood glucose level and postprandial blood glucose level, and therefore a drug containing the MEK inhibitor as an active ingredient It is useful to prevent the onset of type 2 diabetes and the onset of type 2 diabetes from borderline diabetes.

[0031] In addition to the administration of the drug of the present invention, in addition to the administration of the drug of the present invention, α-darcosidase inhibitor (aGI), rapid-acting insulin secretion promotion, for the onset of borderline diabetes and the onset of borderline diabetes to type 2 diabetes Administration of postprandial hyperglycemic drugs such as drugs, diet therapy, exercise therapy, etc. may be combined.

[0032] (3) Method for producing and administering the above drug

The drug containing the wrinkle inhibitor of the present invention as an active ingredient is not particularly limited as long as it contains a compound that inhibits the function of MEK in the Ras / Raf / MEK / ERK pathway. Examples of compounds that inhibit ME function include PD184352, PD98059, U0126, PD 0325901, ARRY-142886, and ARRY-438162 as shown in FIG. These compounds may be synthesized using techniques known to those skilled in the art! /, Or may be commercially available! /.

[0033] The drug containing the MEK inhibitor of the present invention as an active ingredient inhibits MEK function by inhibiting the upstream of MEK in the MAP kinase signal transduction system such as Ras inhibitor, Raiffi harmful agent and the like. Contains compounds! /, Even! /. The Ras inhibitor may be any compound that inhibits the function of Ras. Examples thereof include a farnesyl transferase inhibitor and zoledronic acid. The Ra loading agent may be any compound that inhibits Raf activation, and examples thereof include BAY43-9006 (sorafenib), XL281, and Nexavar. These compounds may be synthesized using techniques known to those skilled in the art or may be commercially available.

[0034] As a pharmaceutically acceptable carrier that can be used for a drug containing a MEK inhibitor, various conventional organic or inorganic carrier substances may be used as a pharmaceutical material. It may contain excipients, lubricants, binders and disintegrants in liquid preparations, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents. Furthermore, if necessary, additives such as usual preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like may be appropriately contained. As the dosage form, oral preparations include, for example, tablets, capsules, granules, powders, fine granules, syrups, sustained-release tablets “capsules” granules, cashews, chewing tablets, or drops. Examples of the force injection include a solution injection, an emulsion injection, and a solid injection.

[0035] The dose of the drug of the present invention varies depending on the age, body weight, indication, or administration'ingestion route, but may be within the range where the above-described effects can be exerted and the resulting side effects are acceptable. If it does not specifically limit.

[0036] As an administration method, for example, in a human or non-human vertebrate, blood glucose level or glucose level test after 2 hours is measured at any time, and when these blood glucose levels show abnormally high levels, the present invention A drug containing an MEK inhibitor as an active ingredient is administered. Especially in humans who are diabetic or borderline, or who have typical symptoms of diabetes (mouthache, polyphagia, polyuria, weight loss), or Hb higher than normal (eg 6.5% or less

Ale

When it is judged as above) or when complications such as diabetic retinopathy are present, a drug containing the MEK inhibitor of the present invention as an active ingredient may be administered.

Example

[0037] The embodiment described above will be specifically described below using examples, but this is an exemplification, and the present invention is not limited to these examples.

In this example, PD 184352 was administered to a type 2 diabetes model mouse, and its blood glucose level and fasting blood glucose and glucose tolerance test 2 hour values were reduced.

[0039] (1) Production of experimental animals

First, 8 weeks old male C57BL / KsJ_db / db mice (CLEA Japan, Inc.) were allowed to freely feed (Lab Lab MR powder (Nippon Agricultural Industrial Co., Ltd.)) with a light / dark cycle of 12 hours. The animals were reared at a temperature of 25 ° C. It is confirmed that the blood glucose level of this mouse is abnormally high. (See the values in Table 2, “Pre-dose”).

[0040] ( ² ) Synthesis of PD18 ⁴ 35 ²

PD 184352 (2- (2-Chioro-4-iodopnenylamino) -N-cyclopropylmethoxy-J, 4_difluoro benzamide) (JS sebolt- Leopold, DT Dudley, R. Herrera, K. Van Becelaere, A. vVi land, RC Gowan, H. Tecle, SD Barrett, A. Bridges, S. Rrzybranowski, WR Leop old and AR ^ altiel, Blockade of the MAP kinase pathway suppresses growth of colo tumors in vivo. Nat. Med. 5 (1999), pp. 810 — 816 ·) was synthesized as follows.

[0041] After 2, 3, 4-trifluorobenzoic acid was coupled to 2_chloro_4_iodoaniline, it was reacted with eye lopropylmethoxyamine in benz otnazoi-1-yi-oxytnpyrrolidinephosphonium nexafluorophosphate, and the final product PD 184352 (2- (2- Chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3, 4-difluorobenzamide) was protected (yield 62%). The structure of the protected compound was confirmed by ^: H NMR and mass spectrometry.

[0042] (3) Measurement of blood glucose level at any time

To this mutant mouse, PD184352 prepared by the method of (2) was mixed with feed and administered orally (dose 200 mg / kg body weight / day) before administration (0 min), after administration 1, 3, 7, On day 14, blood was collected from the tail vein and blood glucose level was measured. The blood glucose level was measured using a simple blood glucose meter (ACCU-CHEK, Roche Diagnostics). Mice that did not receive PD 184352 were used as controls. The results are shown in Table 2.

[Table 2]

*: p 0.05

n = 4

In the control group that did not receive PD184352, the blood glucose level remained elevated at any time, whereas in the group that received PD184352, the blood glucose level at day 1 after PD184352 decreased, and the blood glucose level at 14 days after administration. The value was 2.9 times lower than before administration. Thus, blood glucose could be reduced at any time by administering PD1843452 to a type 2 diabetes model mouse whose blood glucose level was abnormally high at any time.

[0044] Further, on days 17 to 26 after PD 184352 administration, these mice were sacrificed and whole blood was collected, and blood glucose level and insulin level were measured. The blood glucose level was measured using a simple blood glucose meter, and the insulin level was measured using Levis (registered trademark) Insulin-Mouse T (Shibayagi Co., Ltd.). Mice that did not receive PD 184352 were used as controls. The results are shown in Table 3.

[Table 3]

*: p <0.05 (db / db mutant mouse PD 184352 non-treated vs normal mouse)

**: p 0.05 (with db / db mutant mouse PD 184352)

vs db / db mutant mice PD 184352 not administered)

[0045] In the mutant mice that did not receive PD184352, insulin resistance remained elevated, whereas in the mutant mice that received PD184352, the insulin level was approximately 2 on days 17-26 after PD 184352 administration. Doubled.

Thus, administration of PD1843452 to type 2 diabetes model mice with abnormally high blood glucose levels at any time allowed us to reduce blood glucose levels at any time and suppress excessive secretion of insulin. Therefore, it was shown that insulin resistance was improved by administering PD184352.

[0046] (4) Glucose tolerance test method and measurement of fasting blood glucose level and glucose tolerance test for 2 hours

To the above mutant mice, PD184352 prepared by the method (2) was mixed with feed and administered orally (dose was 200 mg / kg body weight / day). 14 days after administration, the mice were fasted for 6 hours, and then a glucose solution (dose: lg / kg body weight) was administered intraperitoneally and before administration (0 minutes) At 30, 60 and 120 minutes after administration, blood was collected from the tail vein and blood glucose level was measured. The blood glucose level was measured using a simple blood glucose meter. Mice that did not receive PD184352 were used as controls. The results are shown in Table 4.

[Table 4]

氺: p 0.05 n = 8

[0047] In the control group not administered PD184352, the fasting blood glucose level before the glucose tolerance test was abnormally high (313 mg / dl), whereas PD184352 administration resulted in a normal fasting blood glucose level (199 mg / dl). Declined.

In the control group, recovery of blood glucose level 2 hours after glucose administration was delayed (2 hour value was 328 mg / dl), whereas in the group administered PD184352, blood glucose level was 2 hours after glucose administration. Although it was slightly higher than before glucose load (0 min) (199 mg / dl), it was closer to the normal value (239 mg / dl).

Thus, fasting blood glucose level and glucose tolerance test 2 hours by administering PD 184352 to type 2 diabetes model mice that showed abnormally high blood glucose levels at any time and glucose recovery test 2 hour values did not recover. The value could be reduced to near the normal value.

[0048] <Example 2: Reduction of fasting blood glucose level and glucose tolerance test 2 hour value in borderline diabetic model mice by administration of PD184352>

In this example, PD 184352 was administered to borderline diabetic model mice, and the fasting blood glucose level and the glucose tolerance test 2-hour value were reduced.

[0049] (1) Production of experimental animals

Purchased 4-week-old C57BL / 6J male mice (Claire Japan), allowed 12 hours of lucid cycle, and freely ingested High Fat Diet32 (Claire Japan) at a temperature of 25 ° C. ~ Reared for 12 weeks. This mouse had normal normal blood glucose levels. Fasting blood glucose levels were different. It showed a normal high value, and the glucose tolerance test 2 hour value only recovered to about twice the normal value (see Table 5 Control values), confirming that this mouse was a borderline diabetes model mouse.

(2) Glucose tolerance test method, fasting blood glucose level and glucose tolerance test 2 hour measurement

PD 184352 prepared by the method of Example 1 (2) was mixed with the feed and orally administered (dosage 200 mg / kg body weight / day) to the borderline diabetes model mouse prepared by the above method. Fourteen days after administration, the mice were fasted for 6 hours, and then a glucose solution (dose was lg / kg body weight) was administered intraperitoneally, before administration (0 min), after administration 30, 60, 120 Blood was collected from the tail vein every minute and blood glucose level was measured. The blood glucose level was measured using a simple blood glucose meter. Mice that did not receive PD184352 were used as controls. The results are shown in Table 5.

[Table 5]

*: p <0.05 n = 4

In the control group that did not receive PD184352, the fasting blood glucose level before the glucose tolerance test showed an abnormally high value (209 mg / dl), whereas PD184352 administration reduced the fasting blood glucose level to a normal value (164 mg / dl). .

In the control group, recovery of blood glucose level 2 hours after glucose administration was delayed (2 hour value was 376 mg / dl), whereas in the group administered PD184352, blood glucose level was 2 hours after glucose administration. It decreased to the same normal value (161 mg / dl) as before glucose load (0 min) (164 mg / dl).

Thus, when the blood glucose level is normal at any time, fasting blood glucose level is abnormally high, and PD 184352 is administered to borderline diabetes model mice that do not recover the glucose tolerance test for 2 hours. Blood glucose level and glucose tolerance test 2 hour value decreased to normal level The power S

[0052] <Example 3: Decrease in blood glucose level, as well as fasting blood glucose level and glucose tolerance test 2 hour value in borderline diabetic model mice by PD0325901 administration>

In this example, PD0325901 was administered to borderline diabetic model mice to reduce the blood glucose level, the fasting blood glucose level, and the glucose tolerance test 2 hour value.

[0053] (1) Production of experimental animals

Example 2 A borderline diabetes model mouse was prepared according to the method described in (1).

[0054] (2) Synthesis of PD0325901

PD0325901 ((R) -N- (2,3_dihydroxypropoxy)-3,4-difluoro- 2- (2-fluoro-4- iodophe nylamino) benzamide) is (R) -0- [ It was synthesized by reacting (2,2_dimethy 卜 1,3_dioxolan_4_yl) methyl] hydroxylamme with 3,4_difluoro_2_ (2_fluoro_4_iodopheny mmo) benzoic acid. The structure of the obtained compound was confirmed by NMR and mass spectrometry.

[0055] (3) Measurement of blood glucose level at any time

PD0325901 prepared by the method of (2) was orally administered to this borderline diabetic model mouse in the feed (dose was 5 mg / kg body weight / day) before administration (0 min), 7 days after administration. Blood was collected from the tail vein and blood glucose level was measured. The blood glucose level was measured using a simple blood glucose meter (ACCU-CHEK, Roche Diagnostics). PD0325901 was not administered! / And a mouse was used as a control. The results are shown in Table 6.

[Table 6]

*: p <0.05

n = 4

In the control group to which PD0325901 was not administered, the blood glucose level at any time was within the normal range, but remained at the upper limit within the normal range, whereas in the group to which PD0325901 was administered, P On day 7 of D0325901 administration, blood glucose level decreased 1.53 times from before administration.

Thus, by administering PD0325901 to borderline diabetic model mice whose normal blood glucose level is normal, the blood glucose level could be lowered at any time while avoiding hypoglycemia.

(4) Glucose tolerance test method, fasting blood glucose level and glucose tolerance test 2 hour measurement

PD0325901 prepared by the method (2) was mixed with the feed and orally administered to the borderline diabetes model mouse prepared by the above method (dose was 5 mg / kg body weight / day). 14 days after administration, the mice were fasted for 6 hours, and then a glucose solution (dose: lg / kg body weight) was administered intraperitoneally, before administration (0 minutes), and 30, 60, 120 minutes after administration. Blood was collected from the tail vein and blood glucose level was measured. The blood glucose level was measured using a simple blood glucose meter. In addition, the mouse | mouth which does not administer PD0325901 was used as control. The results are shown in Table 7.

[Table 7]

Tree: p 0.05 n = 4

Do not administer PD0325901! In the control group, the fasting blood glucose level before the glucose tolerance test was abnormally high (184 mg / dl), but PD0325901 administration resulted in a normal fasting blood glucose level (106 mg / dl). ).

In the control group, recovery of blood glucose level 2 hours after glucose administration was delayed (2 hour value was 260 mg / dl), whereas in the group administered PD0325901, blood glucose level was 2 hours after glucose administration. It decreased to the same normal value (102 mg / dl) as before glucose load (0 min) (106 mg / dl).

Thus, PD0325901 was applied to borderline diabetic model mice whose normal blood glucose level is normal, fasting blood glucose level is abnormally high, and glucose tolerance test 2 hour value does not recover. By administration, it was possible to reduce the fasting blood glucose level and the glucose tolerance test 2-hour value to normal values with the power S.

Industrial applicability

According to the present invention, it has become possible to provide a novel drug effective for type 2 diabetes treatment, borderline diabetes treatment, and diabetes prevention.

Claims

The scope of the claims

[I] A therapeutic agent for type 2 diabetes containing a MEK inhibitor as an active ingredient.

[2] The MEK inhibitor is PD184352 (CI_1040),

Type 2 diabetes treatment.

[3] A therapeutic agent for borderline diabetes containing a MEK inhibitor as an active ingredient.

[4] The therapeutic agent for borderline diabetes according to claim 3, wherein the MEK inhibitor is PD184352 (CI_1040).

5. The borderline diabetes therapeutic agent according to claim 3, wherein the MEK inhibitor is PD0325901.

[6] Glucose tolerance improving agent containing MEK inhibitor as an active ingredient.

7. The glucose tolerance improving agent according to claim 6, wherein the MEK inhibitor is PD184352 (CI_1040).

[8] The glucose tolerance-improving agent according to [6], wherein the MEK inhibitor is PD0325901.

[9] An agent for improving an abnormal fasting blood glucose level comprising a MEK inhibitor as an active ingredient.

10. The fasting blood glucose level abnormality improving agent according to claim 9, wherein the MEK inhibitor is PD184352 (CI_1040).

[I I] The fasting blood glucose level abnormality improving agent according to claim 9, wherein the MEK inhibitor is PD0325901.

[12] A hypoglycemic agent comprising a MEK inhibitor as an active ingredient.

[13] The hypoglycemic agent according to claim 12, wherein the MEK inhibitory power is PD184352 (CI_1040).

14. The hypoglycemic agent according to claim 12, wherein the MEK inhibitor is PD0325901.

[15] The hypoglycemic agent according to claim 12 or 13, wherein the hypoglycemic agent lowers the blood glucose level in a patient having an abnormal blood glucose level at any time.

[16] The postprandial blood glucose level is decreased in patients with borderline diabetes mellitus.

The hypoglycemic agent according to any one of to 14.

[17] The fasting blood glucose level is decreased in patients with borderline diabetes mellitus.

2. The hypoglycemic agent according to any one of 14.

[18] A prophylactic agent for type 2 diabetes comprising a MEK inhibitor as an active ingredient.

[19] The prophylactic agent according to claim 18, wherein the MEK inhibitory power is PD184352 (CI_1040).

20. The preventive agent according to claim 18 or 19, which prevents the onset of type 2 diabetes in patients with borderline diabetes.

[21] The prophylactic agent according to claim 20, wherein the MEK inhibitor is PD0325901.

[22] A preventive agent for borderline diabetes containing a MEK inhibitor as an active ingredient.

[23] The prophylactic agent according to claim 22, wherein the MEK inhibitor is PD184352 (CI_1040).

[24] The prophylactic agent according to claim 22, wherein the MEK inhibitor is PD0325901.

[25] An oral preparation for treating type 2 diabetes or preventing type 2 diabetes, comprising a MEK inhibitor as an active ingredient.

26. The oral preparation according to claim 25, wherein the MEK inhibitor is PD184352 (CI_1040).

[27] An oral preparation for treating borderline diabetes, improving glucose tolerance, improving fasting blood glucose, reducing blood sugar, or preventing borderline diabetes characterized by containing a MEK inhibitor as an active ingredient .

[28] The oral preparation of claim 27, wherein the MEK inhibitor is PD184352 (CI_1040).

[29] The oral preparation of claim 27, wherein the MEK inhibitor is PD0325901.