CN109420175A - Mechanism of blood glucose regulation based on COX - Google Patents
Mechanism of blood glucose regulation based on COX Download PDFInfo
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- CN109420175A CN109420175A CN201710781391.9A CN201710781391A CN109420175A CN 109420175 A CN109420175 A CN 109420175A CN 201710781391 A CN201710781391 A CN 201710781391A CN 109420175 A CN109420175 A CN 109420175A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
Abstract
The invention belongs to biomedicine fields, are related to the mechanism of blood glucose regulation of the multiple target point of COX participation.The present invention provides new prevention or the mechanism for the treatment of diabetes, metabolic syndrome and its related disease.Drug or pharmaceutical composition can protect beta Cell of islet, adjust insulin secretion or increase insulin sensitivity to adjust blood glucose by acting on COX and/or GPR and/or PPAR multiple target point.Thus, the present invention will be to prevent or treatment diabetes, metabolic syndrome and its related disease provide a kind of new way and means.
Description
Technical field
The invention belongs to biomedicine fields, are related to the mechanism of blood glucose regulation of the multiple target point of COX participation.The present invention provides pre-
Anti- or treatment diabetes, metabolic syndrome and its related disease mechanism, drug or pharmaceutical composition can be by acting on
COX and/or GPR and/or PPAR multiple target point protection beta Cell of islet adjust insulin secretion or increase insulin sensitivity to adjust
Save blood glucose.Thus, the present invention will provide a kind of new way to prevent or treating diabetes, metabolic syndrome and its related disease
And means.
Background technique
Diabetes are a kind of energetic supersession diseases, are broadly divided into type 1 diabetes (insulin-dependent diabetes mellitus) and 2 types sugar
Urinate sick (non-insulin-dependent diabetes mellitus).There are about 3.66 hundred million diabetics in the whole world at present, account for the 6.4% of world population,
Middle type 2 diabetic patient accounts for about the 90 ~ 95% of diabetic's sum.
Diabetes can pass through dietary adjustments and exercise treatment.When these cannot alleviate symptom, needs to carry out drug and control
It treats.The drug treatment of diabetes includes: biguanides at present, such as melbine, can reduce the formation of glucose in liver；
Sulfonylurea, such as glibenclamide, being capable of the more insulin of stimulating pancreas β cell secretion；Thiazolidinediones, as pyrrole lattice arrange
Ketone enhances the Purificatiou of insulin by activation peroxisome proliferator activated receptor γ (PPAR- γ)；Alpha-glucosaccharase
Enzyme inhibitor, such as acarbose are able to suppress the generation of glucose in enteron aisle；Glucagon-like-peptide-1 (GLP-1) analog,
Such as Liraglutide, the β cells secrete insulin of pancreas can be promoted；DPP IV (DPP-IV) inhibitor, such as Xi Gelie
Spit of fland is able to suppress the degradation of internal GLP-1.But the method for existing treatment diabetes has certain defect.Such as pancreas islet
Essence injecta and sulfonylurea may cause hypoglycemia and weight gain side effect；Melbine class, alpha-glucosidase inhibit
Agent and GLP-1 analog may cause gastrointestinal side effect；PPAR- gamma agonist may cause weight gain and oedema pair is made
With；DPP-IV inhibitor may cause epipharyngitis, headache and infection side effect.Research for multiple fields is carrying out,
To bring more effective novel blood sugar lowing drug for market.
Cyclooxygenase (cyclooxygenase, COX), also known as prostaglandin endoperoxides synzyme (PGHs), have
Two kinds of isodynamic enzymes of COX-1 and COX-2, be the key that prostaglandin synthesis rate-limiting enzyme, can conversion of arachidonic acid generate it is various before
Column parathyrine and thromboxane A2(TXA2), to generate various physiological and pathological effects.COX-1 is the structure for participating in normal physiological effect
Enzyme, the effects of participating in protection gastrointestinal tract mucosa, adjust renal hemodynamic and promote platelet aggregation；COX-2 is induced enzyme, in physiology shape
Under state, COX-2 can't detect in internal most of tissues, can then be promoted each with great expression under the induction of inflammatory factor
Kind prostaglandin synthesis, the reaction such as mediated pain, inflammation and fever.The inflammation that COX is mediated is that diabetic heart disease occurs
Breaking-out, apoplexy, a main cause of kidney problems and other related complications.
Free-fat acid acceptor (FFAR) is the g protein coupled receptor (GPRs) for going orphanization in recent years.It has determined that at present
Free-fat acid acceptor have G G-protein linked receptor 40(GPR40) family, including GPR40(is also referred to as free-fat acid acceptor 1,
FFA1), GPR41(also referred to as also referred to as free-fat acid acceptor 3, FFA3), GPR43(be also referred to as free-fat acid acceptor 2, FFA2) and
GPR84, GPR120 of other families.GPR40 is to find new galanin-galanin receptors (GALR) Asia
The orphan type GPCR found when type, is highly expressed in the cell line of pancreatic beta cell and excreting insulin.GPR40 can be in conjunction with such as
Palmitic acid, stearic acid, oleic acid, the free fatty acid in the blood plasma such as linoleic acid plus linolenic acid realize various physiological-function.Such as it is long
Chain free fatty acid in conjunction with GPR40 after activate GPR40, in inducing cell calcium ion level increase, enhancing glucose stimulation
The secretion (GSIS) of insulin.GPR40 regulator plays incretin and acts on to promote GSIS, furthermore can also be with a variety of treatments
Diabetes medicament is used in combination.Based on the above, GPR40 agonist can treat diabetes and related indication, especially 2 types sugar
Urine disease, obese insulin are resisted, poor glucose tolerance and other indications.With GPR40 for potential therapy target, hair
Now there is important researching value and application prospect with compound of the transformation with GPR40 agonist activity.
A series of patent application of GPR regulators is disclosed at present, including WO2004041266,
WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097,
WO2009054390, WO2010085525, WO2011008663, WO2009038974, WO2011/140160 etc., the mono- target spot of GPR
The mechanism of blood glucose regulation of mediation has become the hot spot studied at present.
Agent for peroxisome proliferator activated receptor (peroxisome proliferators-activated
Receptors, PPARs) it is ligand activation receptor in nuclear hormone receptor families, its is had discovered that in different species
3 kinds of hypotypes control many intracellular metabolic processes, belong to ligand induced nuclear receptor.PPAR α liver, skeletal muscle, kidney,
It is highly expressed in heart and vascular wall, the expression quantity in fat and cartilage is relatively low.PPAR δ wide expression in vivo,
Brain, stomach, the expression of colon relative high levels.PPAR γ is mainly expressed in fat cell, it is to adjust Adipocyte Differentiation
Important transcription factor.PPAR γ can promote white Adipocyte Differentiation to reduce at numerous small fat cells after being activated
The quantity of big fat cell.Research shows that small fat cell has higher insulin sensitivity for maxicell,
So as to preferably utilize glucose.In addition, molecular biology experiment in recent years has determined that PPAR γ is insulin sensitivity enhancing
The target spot of agent Thiazolidinediones (thiazolidinediones, TZDs) effect.This kind of drug in conjunction with PPAR γ with
After can activate this receptor, to regulate and control a series of important physiology courses.On the one hand the PPAR γ of activation can promote fat
Certain and glucose transport and the expression using related gene, such as 4 (GluT- of insulin receptor and glucose transporter in tissue
4) etc.；On the other hand can inhibit the secretion of in-vivo tumour necrosin (TNF α) and leptin (leptin), mitigate this two
The insulin resistance that kind albumen generates, to play the effect for reducing blood glucose.It can be seen that the activation of PPAR γ and the absorption of glucose
There is very close connection between utilization, therefore, PPAR gamma modulators have become a kind of Remedies for diabetes.
Disclose a series of patent application of PPAR regulators at present, including WO2008143254,
WO2002080936、WO2011059053、CN201310221364.8、CN201310130440.4、CN200780101081.2
The mechanism of blood glucose regulation mediated Deng the mono- target spot of, PPAR has become the hot spot studied at present.
Summary of the invention
The object of the present invention is to provide a kind of prevention or the new machines for the treatment of diabetes, metabolic syndrome and its related disease
System.
New mechanism provided by the invention be adjust COX and/or GPR and/or PPAR multiple target point prevent or treat diabetes,
Application in metabolic syndrome and its related disease.
New mechanism provided by the invention is to adjust COX and/or GPR and/or PPAR multiple target point in protection islet beta cell function
In application.
New mechanism provided by the invention is that adjusting COX and/or GPR and/or PPAR multiple target point are preparing insulin secretion accelerating
Application in agent and insulin sensitizer.
New mechanism provided by the invention is the drug or medicine group by adjusting COX and/or GPR and/or PPAR multiple target point
It closes object and plays biological effect.
The COX includes COX-1 and COX-2 etc., but is not limited to citing range.
The GPR includes GPR40, GPR41, GPR43, GPR84, GPR119 and GPR120 etc., but is not limited to citing model
It encloses.
The PPAR includes PPAR α, PPAR δ and PPAR γ etc..
The drug includes COX regulator and/or GPR regulator and/or PPAR regulator.
The pharmaceutical composition, which is characterized in that the pharmaceutical composition includes that COX regulator and/or GPR are adjusted
Agent and/or PPAR regulator and one or more treatment diabetes medicaments.
The COX regulator includes COX-1 selective depressant, non-selective COX inhibitor, the suppression of COX-2 tendentiousness
Preparation, COX-2 highly selective inhibitor, are exemplified below: aspirin, benorylate, Indomethacin, sulindac, brufen, fluorine ratio
Ibuprofen, fenbufen, Fenbid, Ketoprofen, naproxen, Nabumetone, piroxicam, Meloxicam, celecoxib, Rofe former times
Cloth, watt moral former times cloth, SC 69124, according to appropriate former times cloth etc., but be not limited to citing range.
The GPR regulator include GPR40 regulator, GPR41 regulator, GPR43 regulator, GPR84 regulator,
GPR119 regulator and GPR120 regulator etc., but it is not limited to citing range.
The PPAR regulator include PPAR alfa agonists, PPAR delta agonists, PPAR gamma agonist, PPAR α/δ it is bis- by
Body agonist, PPAR α/γ amboceptor agonist, tri- receptor stimulating agent of PPAR δ/γ amboceptor agonist and PPAR α/δ/γ are lifted
Under such as: Rosiglitazone, Pioglitazone etc., but it is not limited to citing range.
The treatment diabetes medicament, including insulin, insulin analog, promotion islet β cell insulin
Drug, promote peripheral tissues increase glucose utilization drug, inhibit enteron aisle glucose absorption drug, insulin sensitivity enhancing
Agent, the drug for promoting glucose metabolism or the drug for inhibiting renal glucose reabsorption etc., but it is not limited to citing range.
The treatment diabetes medicament, preferred embodiment include insulin, insulin analog, glibenclamide, lattice column
Quinoline ketone, gliclazide, Glipizide, Glimepiride, Repaglinide, Nateglinide, melbine, insoral, Ciglitazone,
Rosiglitazone, Pioglitazone, Liraglutide, Exenatide, Li Sina peptide, albiglutide, acarbose, volt lattice wave sugar, meter Ge
Column alcohol, saxagliptin, Xi Gelieting, vildagliptin, Li Gelieting, Egelieting, song Ge Lieting, Dapagliflozin, canagliflozin,
Ai Gelie net, Ipragliflozin, Luseogliflozin and Tofogliflozin etc., but it is not limited to citing range.
The metabolic syndrome and its related disease is that the generation of the metabolisms such as protein, fat, carbohydrate is disorderly
Random pathological state, including obesity (Despr é s J P, Lemieux I, Alm é ras N. Abdominal obesity
and the metabolic syndrome [M] Overweight and the Metabolic Syndrome.
Springer US, 2006:137-152), hyperglycemia (Grundy S M, Cleeman J I, Daniels S R, et
al. Diagnosis and management of the metabolic syndrome [J]. Circulation,
2005,112 (17): 2735-2752), dyslipidemia (Charlton M. Obesity, hyperlipidemia, and
Metabolic syndrome [J] Liver Transplantation, 2009,15 (S2)), high blood it is glutinous (Irace C,
Scavelli F, Carallo C, et al. Plasma and blood viscosity in metabolic
syndrome [J]. Nutrition, Metabolism and Cardiovascular Diseases, 2009, 19(7):
476-480), high lithemia (Yoo T W, Sung K C, Shin H S, et al. Relationship between
serum uric acid concentration and insulin resistance and metabolic syndrome
[J] Circulation Journal, 2005,69 (8): 928-933), high-fat liver (Marchesini G,
Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and
The metabolic syndrome [J] Hepatology, 2003,37 (4): 917-923) and hyperinsulinemia
(Han T S, Williams K, Sattar N, et al. Analysis of obesity and
hyperinsulinemia in the development of metabolic syndrome: San Antonio Heart
Study [J] Obesity, 2002,10 (9): 923-931) etc., but be not limited to citing range (Grundy S M,
Brewer H B, Cleeman J I, et al. Definition of metabolic syndrome [J].
Circulation, 2004,109 (3): 433-438).
The drug or pharmaceutical composition of the treatment diabetes, metabolic syndrome and its related disease can pass through oral, note
It penetrates, spray, collunarium, eye drip, infiltration, absorption, the method that physically or chemically mediates import body such as muscle, skin and flesh, subcutaneous, quiet
Arteries and veins, mucosal tissue, or body is imported after other material mixings or package, but be not limited to citing range.
When needs, it can also be added in said medicine or pharmaceutical composition one or more pharmaceutically acceptable
Carrier.The carrier includes diluent, excipient, filler, adhesive, wetting agent, the disintegrating agent, absorption of pharmaceutical field routine
Promotor, surfactant, absorption carrier, lubricant etc., but it is not limited to citing range.
The prevention or treatment diabetes, metabolism prepared using the drug or pharmaceutical composition that act on the mechanism as active constituent
Injection, tablet, pulvis, granule, capsule, oral solution, paste, frost can be made in the drug of syndrome and its related disease
The diversified forms such as agent, but it is not limited to citing range.The drug of above-mentioned various dosage forms can be according to the conventional method of pharmaceutical field
Preparation.
Detailed description of the invention
" pharmaceutical composition " is indicated containing one or more COX regulators and/or GPR regulator and/or PPAR regulator and its
The mixture of his chemical constituent, for example pharmaceutical carrier of other chemical constituents and excipient.The purpose of pharmaceutical composition is to promote
Absorption into organism to active constituent plays bioactivity conducive to active constituent in vivo.
Specific embodiment
The present invention is explained in following biology testing example description.
The experimental method of actual conditions usually routinely condition or is built according to commodity manufacturer in test case of the present invention
The condition of view.The reagent in specific source is not specified, for the common agents of market purchase.
Test case 1: the internal hypoglycemic activity of compound can be surveyed by using measurement system as described below in the present invention
It is fixed.
Normal mouse oral glucose tolerance drops experiments have shown that brufen and TAK-875 drug combination than TAK-875 independent medication
Hypoglycemic effect is remarkably reinforced, hence it is evident that reduces the dosage of TAK-875
Normal mouse oral glucose tolerance tests (OGTT): 10 week old cleaning grade ICR mouse (Qinglongshan animal experimental center, Jiangsu
Nanjing), 20~24 g of weight, male is randomly divided into 4 groups, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose
Element), group 2: positive drug control group (TAK-875:20 mg/kg), group 3: brufen (25 mg/kg) combines TAK-875(10 mg/
Kg), organize 4: brufen (50 mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, and the equal oral administration gavage of each group is given
Medicine, docking take blood, measure blood glucose value.Then blank solvent, TAK-875, brufen joint TAK- are given in stomach-filling to 4 groups of mouse respectively
Measurement blood glucose value is denoted as 0 min after 875 and brufen, 30 min, and stomach-filling immediately later is given glucose (2 g/kg), and in
15,30,60,120 min measure blood glucose value.It the results are shown in Table 1.
Table 1: influence (± SD, n=8) of the compound to normal mouse oral glucose tolerance
Test case 2: the internal hypoglycemic activity of compound can be by using measurement system measurement as described below in the present invention.
Diabetes C57BL/6 mouse oral sugar tolerance can be controlled effectively experiments have shown that brufen and TAK-875 drug combination
The blood glucose of diabetes C57BL/6 mouse processed, reduces the dosage of TAK-875
Diabetes C57BL/6 mouse oral sugar tolerance tests (OGTT): diabetes C57BL/6 mouse, and 30~36 g of weight is male
Property, 4 groups are randomly divided into, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose), group 2: positive drug control group
(TAK-875:20 mg/kg), group 3: brufen (25 mg/kg) combines TAK-875(10 mg/kg), group 4: brufen (50
Mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, and the equal oral administration gavage administration of each group, docking takes blood, measures blood
Sugar value.Then blank solvent, TAK-875, brufen joint TAK-875 and brufen, 30 min are given in stomach-filling to 4 groups of mouse respectively
Measurement blood glucose value is denoted as 0 min afterwards, and glucose (1.5 g/kg) is given in stomach-filling immediately later, and in 15,30,60,120 min
Measure blood glucose value.It the results are shown in Table 2.
Table 2: influence (± SD, n=8) of the compound to diabetes C57BL/6 mouse oral sugar tolerance
Test case 3: the internal hypoglycemic activity of compound can be by using measurement system measurement as described below in the present invention.
Normal mouse oral glucose tolerance is experiments have shown that brufen and Pioglitazone drug combination, than Pioglitazone independent medication
Blood sugar decreasing effect is remarkably reinforced, hence it is evident that reduces the dosage of Pioglitazone
Normal mouse oral glucose tolerance tests (OGTT): 10 week old cleaning grade ICR mouse (Qinglongshan animal experimental center, Jiangsu
Nanjing), 20~24 g of weight, male is randomly divided into 4 groups, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose
Element), group 2: positive drug control group (Pioglitazone: 3.0 mg/kg), group 3: brufen (25 mg/kg) combines Pioglitazone (1.5
Mg/kg), organize 4: brufen (50 mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, the equal oral administration gavage of each group
Administration, docking take blood, measure blood glucose value.Then blank solvent, Pioglitazone, brufen joint are given in stomach-filling to 4 groups of mouse respectively
Pioglitazone and brufen, measurement blood glucose value is denoted as 0 min after 30 min, and glucose (2 g/kg) is given in stomach-filling immediately later,
And blood glucose value is measured in 15,30,60,120 min.It the results are shown in Table 3.
Table 3: influence (± SD, n=8) of the compound to normal mouse oral glucose tolerance
Test case 4: the internal hypoglycemic activity of compound can be by using measurement system measurement as described below in the present invention.
Diabetes C57BL/6 mouse oral sugar tolerance, can be effective experiments have shown that brufen and Pioglitazone drug combination
The blood glucose for controlling diabetes C57BL/6 mouse, reduces the dosage of Pioglitazone
Diabetes C57BL/6 mouse oral sugar tolerance tests (OGTT): diabetes C57BL/6 mouse, and 30~36 g of weight is male
Property, 4 groups are randomly divided into, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose), group 2: positive drug control group
(Pioglitazone: 3.0 mg/kg), group 3: brufen (25 mg/kg) combines Pioglitazone (1.5 mg/kg), group 4: brufen
(50 mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, and the equal oral administration gavage administration of each group, docking takes blood, surveys
Determine blood glucose value.Then blank solvent, Pioglitazone, brufen joint Pioglitazone and brufen are given in stomach-filling to 4 groups of mouse respectively,
Blood glucose value is measured after 30 min is denoted as 0 min, stomach-filling immediately later is given glucose (1.5 g/kg), and in 15,30,60,
120 min measure blood glucose value.It the results are shown in Table 4.
Table 4: influence (± SD, n=8) of the compound to diabetes C57BL/6 mouse oral sugar tolerance
Test case 5: the internal hypoglycemic activity of compound can be by using measurement system measurement as described below in the present invention.
Normal mouse oral glucose tolerance can effectively control diabetes experiments have shown that brufen and melbine drug combination
The blood glucose of C57BL/6 mouse reduces the dosage of melbine
Normal mouse oral glucose tolerance tests (OGTT): 10 week old cleaning grade ICR mouse (Qinglongshan animal experimental center, Jiangsu
Nanjing), 20~24 g of weight, male is randomly divided into 4 groups, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose
Element), group 2: positive drug control group (100 mg/kg of melbine), group 3: brufen (25 mg/kg) combines melbine (50
Mg/kg), organize 4: brufen (50 mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, the equal oral administration gavage of each group
Administration, docking take blood, measure blood glucose value.Then compound is given in stomach-filling to 4 groups of mouse respectively, and measurement blood glucose value is denoted as after 30 min
0 min, later stomach-filling immediately are given glucose (2 g/kg), and measure blood glucose value in 15,30,60,120 min.It the results are shown in Table
5。
Table 5: influence (± SD, n=8) of the compound to normal mouse oral glucose tolerance
Test case 6: the internal hypoglycemic activity of compound can be by using measurement system measurement as described below in the present invention.
Diabetes C57BL/6 mouse oral sugar tolerance, can be effective experiments have shown that brufen and melbine drug combination
The blood glucose for controlling diabetes C57BL/6 mouse, reduces the dosage of melbine
Diabetes C57BL/6 mouse oral sugar tolerance tests (OGTT): diabetes C57BL/6 mouse, and 30~36 g of weight is male
Property, 4 groups are randomly divided into, group 1: blank control group (blank solvent: 0.5% carboxymethyl cellulose), group 2: positive drug control group
(100 mg/kg of first biguanides), group 3: brufen (25 mg/kg) combines melbine (50 mg/kg), group 4: brufen (50
Mg/kg), every group 8, mouse is deprived of food but not water 12 hours before testing, and the equal oral administration gavage administration of each group, docking takes blood, measures blood
Sugar value.Then blank solvent, melbine, brufen joint melbine and brufen are given in stomach-filling to 4 groups of mouse respectively, and 30
Blood glucose value is measured after min and is denoted as 0 min, and glucose (1.5 g/kg) is given in stomach-filling immediately later, and in 15,30,60,120
Min measures blood glucose value.It the results are shown in Table 6.
Table 6: influence (± SD, n=8) of the compound to diabetes C57BL/6 mouse oral sugar tolerance
Claims (10)
1. the mechanism of blood glucose regulation based on COX and/or GPR and/or PPAR multiple target point.
2. drug or pharmaceutical composition based on the preparation of the mechanism of blood glucose regulation of COX and/or GPR and/or PPAR multiple target point are pre-
Application in anti-or treatment diabetes, metabolic syndrome and its related disease.
3. drug or pharmaceutical composition based on COX and/or GPR and/or PPAR multiple target point are in the medicine for preparing insulin secretion accelerating
Object and/or prepare insulin sensitivity enhancing drug and/or preparation protection beta Cell of islet drug in application.
4. COX described in claim 1-3 includes COX-1 and COX-2 etc., but is not limited to citing range；The GPR includes
GPR40, GPR41, GPR43, GPR84, GPR119 and GPR120 etc., but it is not limited to citing range；The PPAR includes PPAR
α, PPAR δ and PPAR γ etc..
5. drug described in claim 2-3 includes COX regulator and/or GPR regulator and/or PPAR regulator；Described
Pharmaceutical composition includes COX regulator and/or GPR regulator and/or PPAR regulator and one or more treatment Rezulins
Object.
6. COX regulator described in claim 5 includes COX-1 selective depressant, non-selective COX inhibitor, COX-2
Tendentiousness inhibitor or COX-2 highly selective inhibitor etc., are exemplified below: aspirin, benorylate, Indomethacin, sulindac,
Brufen, fenbufen, Fenbid, Ketoprofen, naproxen, Nabumetone, piroxicam, Meloxicam, is filled in and carrys out former times Flurbiprofen
Cloth, rofecoxib, watt moral former times cloth, SC 69124, according to appropriate former times cloth etc., but be not limited to citing range；The GPR regulator includes
GPR40 regulator, GPR41 regulator, GPR43 regulator, GPR84 regulator, GPR119 regulator or GPR120 regulator etc.,
But it is not limited to citing range；The PPAR regulator include PPAR alfa agonists, PPAR delta agonists, PPAR gamma agonist,
PPAR α/δ amboceptor agonist, PPAR α/γ amboceptor agonist, PPAR δ/γ amboceptor agonist and PPAR α/δ/γ tri- by
Body agonist, is exemplified below: Rosiglitazone, Pioglitazone etc., but is not limited to citing range.
7. treatment diabetes medicament described in claim 5, including insulin, insulin analog, promotion islet β cell
The drug of insulin promotes peripheral tissues to increase the drug of glucose utilization, inhibit drug, the insulin of enteron aisle glucose absorption
Sensitizer, the drug for promoting glucose metabolism or the drug for inhibiting renal glucose reabsorption etc., preferred embodiment includes pancreas
Island element, insulin analog, glibenclamide, gliquidone, gliclazide, Glipizide, Glimepiride, Repaglinide, that lattice
Column how, melbine, insoral, Ciglitazone, Rosiglitazone, Pioglitazone, Liraglutide, Exenatide, Li Sina peptide,
Albiglutide, acarbose, volt lattice wave sugar, Miglitol, saxagliptin, Xi Gelieting, vildagliptin, Li Gelieting, A Ge
Arrange spit of fland, song Ge Lieting, Dapagliflozin, canagliflozin, Ai Gelie only, Ipragliflozin, Luseogliflozin and
Tofogliflozin etc., but it is not limited to citing range.
8. drug described in claim 2-2 or pharmaceutical composition can pass through oral, injection, injection, collunarium, eye drip, infiltration, suction
It receives, the method that physically or chemically mediates imports body such as muscle, skin and flesh, subcutaneous, vein, mucosal tissue or by other substances
Body etc. is imported after mixing or package, but is not limited to citing range.
9. one or more pharmaceutically acceptable loads can also be added in drug described in claim 2-3 or pharmaceutical composition
Body etc., the carrier include diluent, excipient, filler, adhesive, wetting agent, the disintegrating agent, absorption of pharmaceutical field routine
Promotor, surfactant, absorption carrier, lubricant etc., but it is not limited to citing range.
10. drug described in claim 2-3 or pharmaceutical composition, the drug or pharmaceutical composition can be made into injection, tablet,
The diversified forms such as pulvis, granule, capsule, oral solution, paste, creme, but it is not limited to citing range.
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