CN108653260A - A kind of purposes of the ligand of Farnesoid X receptor - Google Patents
A kind of purposes of the ligand of Farnesoid X receptor Download PDFInfo
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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
Abstract
The present invention relates to compound Vidofludimus and its pharmaceutically acceptable salt, the application in the drug or health products for preparing prevention and treatment metabolic disease.The compound is the conditioning agent of nuclear receptor Farnesoid X receptor (FXR), can prepare prevention and treatment diabetes, applied in the drug or health products of the diseases such as obesity, fatty liver, hepatic sclerosis, hyperglycemia, angiocardiopathy, hypertriglyceridemia, hypercholesterolemia, hepatic injury, transaminase increase, cholestasia, gall stone, atherosclerosis.
Description
Technical field
The present invention relates to a kind of purposes of compound Vidofludimus in the fields such as medicine and health products.
Background technology
The diseases such as diabetes, obesity, fatty liver, hepatic sclerosis, hyperglycemia, hyperlipidemia, hepatic injury, kidney trouble die harm
The major disease or common disease and frequently-occurring disease of human health find that the new drug for preventing or treating these diseases will be with important society
It can be worth and huge economic value.
Diabetes are that one group of complication is up to more than 100 kinds, the metabolic disease characterized by chronic hyperglycemia.Long-term blood glucose
Increasing can cause big blood vessel, capilary to be damaged and jeopardize the organs such as the heart, brain, kidney, peripheral nerve, eyes, foot.Concurrent heart and brain blood
Pipe disease and kidney trouble are the main reason for causing diabetic dead.Amputation ratio is also significantly larger than in diabetic
Non-diabetic patients.Diabetic complication can be divided into acute and chronic two major classes.Diabetic Acute complication is mainly due to blood
Sugar is excessively high cause sugar, fat and protein metabolism disorder caused by, including diabetic ketoacidosis, Hyperglycemic hyperosmolar status, breast
Acid acid poisoning etc..Chronic complicating diseases of diabetes is the main reason for diabetes disable, is lethal, includes mainly：1) big blood vessel is simultaneously
Send out disease, such as the lesion of the cerebrovascular, angiocarpy and lower limb vascular.2) microvascular complication, such as renal lesions and eyeground pathological changes.3)
Neuropathy, such as sensory nerve lesion, kinesitherapy nerve lesion, autonomic neuropathy.The chronic complicating diseases of diabetes include sugar
The sick nephrosis of urine, diabetic retinopathy, diabetic uveitis, diabetic cataract, diabetes, diabetes painstaking effort
Pipe complication, coronary heart disease, cerebrovascular disease etc..Atherosclerosis, hyperglycemia, high convergency pressure, high cholesterol, low-density lipoprotein
Increase, high-density lipoprotein decline etc. be diabetes coronary heart disease morbidity risk factor.Diabetic cerebrovascular disease is main
Show as cerebral arteriovenous malformation, ischemic cerebrovascular disease, cerebral hemorrhage, encephalatrophy etc..
When human body feed heat is more than consumption of calorie, for waste heat with storage as fat in internal, amount is more than just
Normal physiological requirements amount, and up to certain value when develop into obesity then.Compared to non-obese person, obesity patient and premature coronary heart disease and height
The probability of blood pressure obviously increases.Mostly with the disorder of metabolism while obesity lipid metaboli enlivens, it may appear that hypertriglyceridaemia
The symptoms such as disease, hypercholesterolemia.Obesity carbohydrate metabolism disturbance shows as the exception and diabetes of sugar tolerance.
The main reason for atherosclerosis is coronary heart disease, cerebral infarction, peripheral vascular disease.Lipidosis is artery congee
The lesion basis of sample hardening.Hypercholesterolemia is the pathogenic sexual factor of atherosclerosis.Hypertension is also Atherosclerosis
The pathogenic sexual factor changed, hypercholesterolemia and hypertension reciprocal causation, often exist simultaneously.Diabetic often has blood courage solid
The performance that alcohol, triglycerides increase.Blood lipid-lowering medicine is one of the means for treating atherosclerosis.
Cardiovascular and cerebrovascular disease refers to hyperlipidemia, blood is sticky, the heart caused by atherosclerosis, hypertension etc.
The ischemic or hemorrhagic disease that dirty, brain and body tissue occur.The cardiovascular and cerebrovascular disease cause of disease mainly have atherosclerosis,
Hypertensive cerebral arteriosclerosis, hypertension, hyperlipidemia, diabetes and blood constituent factor etc..
Metabolic syndrome shows as the substances such as the protein, fat, carbohydrate of human body and metabolic disorder occurs, and is one group
Complicated metabolic disorder disease group, clinical manifestation be obesity, Anomalous lipid metablism, hypertension, diabetes, insulin resistance and/or
Abnormal glucose tolerance.It is the risk factor for leading to diabetes cardiovascular and cerebrovascular disease.Metabolic syndrome patients often exist simultaneously more
Kind of metabolic disorder, including obesity, hyperglycemia, hypertension, dyslipidemia, high blood stick, high lithemia, liver incidence high in fat and high pancreas
Island element mass formed by blood stasis, these metabolic disorders are the pathologic basis of the heart, cerebrovascular disease and diabetes.Therefore diabetes are also that metabolism is comprehensive
One of component part of simulator sickness.Metabolic syndrome has common prevention and remedy measures, prevents a kind of metabolic disorder, also just has
Conducive to the prevention of other metabolic disorders.
Metabolic disorder be body to the digestion, absorption, excretion of substance occur pathologic, uncoordinated unbalanced supply-demand shape
State.It can be the disorder of one or more substances.Various metabolism state disorders are different.Carbohydrate metabolism disturbance causes diabetes,
Disorders of lipid metabolism causes hyperlipidemia etc..
In conclusion the accumulation of hyperglycemia, hyperlipidemia, liver fat is diabetes, obesity, angiocardiopathy, artery congee
The cardinal symptom of the diseases such as sample hardening, metabolic syndrome, metabolic disorder, and also result in serial related complication disease.
Fatty liver refer to due to various reasons caused by the excessive lesion of fat accumulation in liver cell.Fatty liver is because including
Obesity fatty liver, alcoholic fatty liver, quick weight-lossing fatty liver, dystrophic fatty liver, diabetic fatty liver, drug
Fatty liver caused by property fatty liver, pregnancy fatty liver and other diseases.Non-alcohol fatty liver (NAFLD) refers to removing
Fatty over-deposit is that the clinical pathology of main feature integrates in liver cell caused by outer alcohol and other specific damage liver factors
Sign.Can there is overweight and (or) Abdominal obesity, fasting blood-glucose to increase, the metabolic syndromes such as blood fat disorder, hypertension it is related
Symptom.Liver fatization can allow blood vessel constriction, lead to hepatic tissue hypoxic-ischemic, so as to cause degeneration necrosis, the liver of liver cell
Dirty fibrosis hyperplasia, leads to hepatic sclerosis.
Biliary cirrhosis is because of biliary obstruction, and hepatic sclerosis caused by cholestasis divides primary biliary cirrhosis
(PBC) and secondary biliary cirrhosis.Cholestasis is one group caused by disorders of bile production or/and bile flow disorders
The common clinical symptoms of disease also known as cholestatic syndrome.Cholestasis of pregnancy disease be only pregnant woman can just occur it is special
Illness, before itch occurs or serum glutamic pyruvic transminase increases preceding Serum Conjugated Cholic Acids and first increases, and is the reliable finger of early diagnosis
Mark.Also serum total bilirubin increases, serum bile acid increases, alkaline phosphatase activities increase, transaminase can light, moderate increase
Etc. indexs symptom.
The factors such as a variety of physics, chemistry, biology can cause hepatic injury.The result of damage frequently can lead to hepatonecrosis, fat
Fat liver, cholestasis, liver fibrosis, hepatic sclerosis etc., fibrosis therein, the i.e. over-deposit of each ingredient of liver cell epimatrix
And abnormal distribution.Collagen (collagen) is the most important ingredient of extracellular matrix, and collagen deposition is typical feature
One of, the expression for detecting collagen gene can be as liver fibrosis, one of the index of hepatic sclerosis.
There are many aminopherases in human body, the transaminase for detecting liver function clinically by blood test mainly has two
Kind, one kind being alanine aminotransferase (ALT)；Another kind is aspartic transaminase (AST).In liver function test chemical examination,
Transaminase height illustrates liver function damage.Alkaline phosphatase (ALP) is also one of the index of liver function.
The effect of most of small-molecule drugs is by combining one or more protein " target ", and then adjusting these
The function of " target " and signal transduction play a role.Therefore, drug, which provides the identification of protein target, understands drug
Act on the basis of action.The target proteins matter for illustrating these drugs will provide theories integration for effective treatment of disease, be important
The research and development of new drug provide effective means.
Nuclear receptor (nuclear receptor) is one group of transcription factor regulated and controled by smaller ligand.Ligand small molecule
Compound plays an important role in terms of the activity for adjusting nuclear receptor.It is induced by ligand, the conformation of nuclear receptor changes, and passes through
The shape, size and specific hydrophobic or hydrophilic amino acid of its ligand binding pocket are adjusted to identify simultaneously binding partner, and controls it
In conjunction with intensity and specificity；Various ligand induced nuclear receptors carry out corresponding conformation change and are also adapted for recruiting combination or release
Put different counselor works, these counselor works include co-activator p160 families (also cry steroid receptor co-activation because
Sub (steroid receptor coactivators, english abbreviation SRC), Corepressors such as vitamin A acid and thyroid hormone
The receptor silence adjustment factor (english abbreviation SMART) and core Corepressors N-CoR.These counselor works so determine core by
Body activates or inhibits state, and the expression by regulating and controlling target gene influences physiology or pathologic function.Therefore, the function of nuclear receptor with
The ligand that it is combined is closely related.
Gene by nuclear receptor regulation and control plays in many physiology courses such as the growth of body inner cell, differentiation, development, metabolism
Important function.These gene regulations are more closely related with serial major disease such as diabetes, tumour, inflammation, angiocardiopathy etc..
Therefore, nuclear receptor has become important medicament research and development target.Now before global drug on hundred situation of selling well lists 13% be all with core by
Body is target protein target, has absolutely proved the huge medicament research and development value of nuclear receptor and its ligand and important economy and society valence
Value.
Farnesoid X receptor FXR (Farnesoid X Receptor) is the important member in nuclear receptor superfamily, and FXR is being fed
There is high expression in the liver of newborn animal, small intestine, kidney and prostate.Farnesol (farnesoids) and vitamin A acid are found earliest
(retinoids) transcriptional activity of FXR can be activated, but they are all very low to the affinity of FXR, therefore FXR is listed in always orphan
Youngster's nuclear receptor.Until Steven seminars in 2000 are just found that the high-affinity of FXR, artificial synthesized ligand for the first time
GW4064.Then, people have carried out a series of research using GW4064 to the biological function of FXR, find FXR in sugared generation
It thanks, have the function of important in terms of the adjustings such as lipid metaboli, cholesterol-cholic acid metabolism, biliary cycle, FXR is also hard in liver regeneration, liver
Change, Adipose Differentiation, anti-oxidant, anti-aging etc. have important regulating and controlling effect.Nuclear receptor is a kind of transcription factor of ligand activation.
The ligand-mediated pharmacological action principle of FXR is ligand by being combined with FXR, and it is (or auxiliary that induction FXR recruits all kinds of co-activators
Inhibiting factor) adjust downstream target gene.FXR involves many relevant signal paths of metabolism, becomes treatment metabolic disease such as
Hypertriglyceridemia, hypercholesterolemia, hyperglycemia, cholestasia, gall stone, fatty liver, the hard liver fibrosis of liver, artery congee
The outstanding drug target molecules such as sample hardening, angiocardiopathy and diabetes.
A variety of human liver diseases can cause cholestasis, such as primary biliary cirrhosis, primary sclerotic courage
Guan Yan, cystic fibrosis and intrahepatic cholestasis of pregnancy.It is relevant that its bile acid transport can be raised when activating FXR in liver
Expression of target gene, to promote removing and the inhibition bile acid biosynthesis of bile acid.Bile acid intestines liver cycle be conducive to human body from
Lipid and liposoluble vitamin are absorbed in enteron aisle, and is conducive to remove liver inner cholesterol, and toxin and liver metabolism by-product are such as
Bilirubin.
FXR can adjust bile synthesis and bile by adjusting cholic acid synthesis, the relevant serial genes of bile transport expressing
Hepato-enteric circulation, protection liver function, protection liver organization in terms of play a crucial role.The mouse tool that FXR is knocked out
There is cholestatic liver disease.In cholestasis mouse model caused by bile duct ligation and α-naphthalene isothiocyanate, give
GW4064 treatments can lower gene related with hepatic lesion, and raise the related gene such as bile salt for participating in bile acid transport
Rear pump (BSEP) and organic solvent transporter (OST α/βs) etc..This shows that FXR ligands can be used for treating cholestasis class
Liver diseases.The treatment that FXR agonists can help to cholestatic liver disease, such as cholestasis are given, hepatic injury, capsule are fine
Dimensionization and intrahepatic cholestasis of pregnancy.
Since FXR ligands can influence bile acid biosynthesis and lipid-metabolism by regulating and controlling FXR so that they can be in bile acid
Hepatic injury caused by preventive and therapeutic action, such as bile acid, fatty liver, liver cancer and artery are played in relevant liver diseases
Atherosis and angiocardiopathy.In addition, learning that FXR is adjusting glycerine by the research of the mouse to wild type and FXR knockouts
Three esters, blood fat, cholesterol, glycometabolism play a significant role with bile acid stable state.Hypertriglyceridemia is the weight of coronary heart disease
Inducement is wanted, therefore it is a strategy for preventing and treating coronary heart disease well to reduce hypertriglyceridemia.It is high sweet
Oily three ester mass formed by blood stasis are mainly due to the inverse relationship between serum triglyceride and high-density lipoprotein cholesterol, because of low-level
High-density lipoprotein can increase the risks of vascular diseases.Bile acid can reduce serum triglyceride by activating FXR, under
Adjust the related gene of SREBP-1c and lipid synthesis.Therefore, FXR ligands can be used to treat or prevent is lured by hypertriglyceridemia
The coronary heart disease of hair.
There is the mouse that FXR is knocked out sugar not tolerate the feature with insulin resistance.In addition to GW4064, current research finds one
The novel FXR ligands ivermectin of kind has the function of adjusting glycolipid stable state, and this effect is FXR dependences.Therefore,
FXR be treat or prevent hyperglycemia, high cholesterol, obesity, diabetes and glycolipid metabolism related diseases drug target.
Due to the key effect that FXR is played in lipid-metabolism, the ideal of non-alcoholic fatty liver disease drug is become
Target spot.Activation FXR can be lowered and be participated in aliphatic acid synthesis in liver, lipid generates, the expression of gluconeogenesis related gene, and be alleviated
The steatosis of fat mouse.As the ligand of FXR, the associated metabolic that avermectin can effectively adjust obesity mice similar to object refers to
Mark, including liver lipids deposition is reduced, serum cholesterol and blood glucose level are lowered, non-alcohol fatty liver is improved.To sum up
Described, FXR has become improvement non-alcoholic fatty liver disease, the important target spot of hepatic sclerosis.
Hypercholesterolemia and dyslipidemia are the major incentives of angiocardiopathy and atherosclerosis, show as increasing
Plasma triglyceride (TG) and the high-density lipoprotein cholesterol (HDL-C) that reduces, while with fat, blood glucose rise and height
A kind of metabolic syndrome of blood pressure.Since the activation of FXR can effectively treat the hyperlipidemia of ApoE-/- model mice, explanation
It can delay the development of atherosclerosis.Therefore, FXR ligands can be used for preventing and treating atherosclerosis and cardiovascular disease
Disease.
FXR also plays vital effect in the fatty liver caused by aging, in the liver of long-lived mouse
The expression of FXR and activity are all increased, this all prompts the association between our FXR and longevity.Activation FXR can alleviate aging
Caused liver regeneration obstacle.These promote liver regeneration simultaneously research shows that treating to have in disease caused by aging using FXR
Extend the effect in service life.
It is beneficial to bone metabolism to adjust FXR by ligand, the formation of sclerotin, differentiation and absorption is adjusted, prevents bone loss
With raising bone mass, imply that FXR ligands have the function for the treatment of bon e formation relevant disease such as osteoporosis, osteoproliferation.
Blood urea nitrogen is one of renal function leading indicator, and blood urea nitrogen is excessively high, indicates various parenchymal lesion of the kidney, acute and chronic
Occupancy and destructive lesion and uremia etc. in renal failure, kidney.Have been reported that display, FXR's effectively reduces with physical efficiency
Blood urea nitrogen is horizontal, shows effect of the ligand compound in treatment kidney trouble and protection renal function of FXR.
Although important function of the FXR in human diseases has obtained suitable concern, have for the therapeutic effect of FXR ligands
It waits for further studying.Due to bile acid such as CA, CDCA are low with the affinity of FXR and can raise LDL cause apparent hepatotoxicity wind agitation from
And limit their applications on human body.CDCA equally can be incorporated into ileal bile acid binding protein (I-BABP), bile acid
Transport protein and other protein.The FXR ligands of many synthesis have also been reported, but due to its side effect and uncertain biology
Availability limits their use.Therefore, it is necessary to find FXR Novel Ligands, the corresponding compound of synthesis optimizing is established and is closed
Suitable system to treat FXR adjusting disease.
Term " FXR adjusting control agents " described herein or " FXR ligands " refer to any active compound that can adjust FXR,
Nuclear receptor including complete activator, partial agonist, antagonist, inverse agonist, or selectivity adjusts molecule.FXR ligands
Classification is that the ability and tune of different counselor works are raised according to these compounds binding pattern different from FXR, induction FXR
It saves transcription or posttranslational modification and determines.Posttranslational modification, such as SUMOization and phosphorylation, also respectively with transcriptional activation or transcription
Inhibit associated.
Vidofludimus, following name also illustrate that the compound：4SC‐101；SC12267；2‐[[(3‐Fluoro‐3'‐
Methoxy [1,1'-biphenyl] -4-yl) amino] carbonyl] -1-cyclopentene-1-carboxylic acid,
Chinese is 2- [[(the fluoro- 3'- methoxyl groups of 3- [1,1'- biphenyl] -4- bases) amino] carbonyl] -1- cyclopentene -1- carboxylic acids；2‐[(3‐
Fluoro-3'-methoxybiphenyl-4-yl) carbamoyl] cyclopent-1-ene-1-carboxylic acid, in
Text is 2- [(the fluoro- 3'- methoxyl biphenyls -4- bases of 3-) carbamoyl] amyl- 1- alkene -1- carboxylic acids of ring；Molecular formula C20H18FNO4,
Structural formula is as follows：
It has not yet to see and is reported in terms of Metabolism regulation the effect of about Vidofludimus.
Invention content
The purpose of the present invention is to provide a kind of compound Vidofludimus to prepare prevention and treatment metabolic disease
Drug or health products in application.
The metabolic disease refer to hyperglycemia, hyperlipemia, hypercholesterolemia, hypertriglyceridemia, diabetes,
Obesity, and angiocardiopathy, atherosclerosis, liver fibrosis, hepatic sclerosis, Metabolic syndrome caused by above-mentioned disease
The total hair disease of sign, metabolic disorder and relevant disease；It is the disease (liver disease) of liver, Fatty Liver Disease (hepatic steatosis), non-
Alcoholic fatty liver disease, hepatic sclerosis, liver fibrosis, chronic and acute liver failure；Biliary cirrhosis, cholestasis,
The total hair disease of cholelith atherosclerosis and relevant disease.
The disease of the liver refers to the liver diseases with hepatic injury symptom.
The application is compound Vidofludimus for treating the application during transaminase increases.
The metabolic disease is the metabolic disease that nuclear receptor FXR is mediated, including hyperglycemia, hyperlipemia, high glycerine
Three ester mass formed by blood stasis, hypercholesterolemia, diabetes, obesity, fatty liver, hepatic sclerosis, hepatic injury, angiocardiopathy, artery are athero-
Hardening, cholestasia, gall stone and relevant disease total hair disease.
The application, it is characterised in that Vidofludimus can be the available salt product of pharmacy.
The application, it is characterised in that Vidofludimus can exist with sodium salt or calcium salt forms.
It is demonstrated experimentally that Vidofludimus and its salt product treatment hyperglycemia, hyperlipidemia, hypercholesterolemia,
The effect of the diseases such as hypertriglyceridemia, diabetes, obesity.Utilize diabetes, obesity models mouse db/db and obesity
Disease mouse ob/ob after Vidofludimus or its salt product is injected intraperitoneally, detects related-metabolism index.The result shows that compared to sky
Model mice liver/weight ratio of white control, Vidofludimus or the processing of its salt product, glucose in serum, triglycerides,
Cholesterol levels are substantially reduced.Biochemistry detection result shows, the mouse liver group of Vidofludimus or its salt product processing group
The triglycerides and total cholesterol level knitted are reduced compared with control group.Mouse liver histotomy HE dyeing and oil red coloration result table
Bright, fatty amount is significantly lower than control group mice in the mouse liver tissue of Vidofludimus or its salt product processing group.This
It is a little results showed that Vidofludimus treatment hyperglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,
Diabetes, obesity, Fatty Liver Disease (hepatic steatosis), nonalcoholic fatty liver disease, and caused by these diseases
Angiocardiopathy, atherosclerosis, hepatic sclerosis, liver fibrosis, chronic and acute liver failure, metabolic syndrome, generation
Thank to the curative effect in disorderly and relevant disease total hair disease.
Experiment demonstrates the liver protecting of Vidofludimus and its salt product using liver injury model mouse and repairs work(
Energy.The present invention is to continuous 5 days intraperitoneal injection Vidofludimus of C57B6/J mouse or its salt product, and then injection is excessive to second
Acylamino- phenol (N-acetyl-para-aminophenol is abbreviated as APAP) causes hepatic injury, for 24 hours rear testing result.As a result table
It is bright, in the case where control group shows severe liver injury, inject Vidofludimus or the mouse liver shape of its salt product
State and liver function are acted normally.Show Vidofludimus and its salt product prevention and treatment liver disease (liver disease),
Curative effect in liver damage disease.
It is demonstrated experimentally that Vidofludimus and its salt product, which can obviously adjust cholic acid, recycles relevant FXR target genes and glue
Former protein gene expression, show Vidofludimus and its salt product biliary cirrhosis, liver fibrosis, cholestasis,
Effect in the total hair disease of cholelith atherosclerosis and relevant disease.
It is demonstrated experimentally that Vidofludimus and its salt product can be combined with nuclear receptor FXR, induction FXR raise auxiliary adjusting because
Son；And Vidofludimus and its salt product can adjust the expression of the target gene such as BSEP and OST α of FXR, show
Vidofludimus and its salt product are the small molecules " adjusting control agent " or " FXR ligands " of nuclear receptor FXR, can be by combining target
FXR adjust the metabolism such as glycometabolism, lipid metaboli, the metabolism of cholesterol-cholic acid that FXR is participated in body, liver fibrosis, hepatic sclerosis,
The function of Adipose Differentiation etc. indicates hyperglycemia, hypertriglyceridaemia that Vidofludimus and its salt product mediate in FXR
Disease, hypercholesterolemia, diabetes, obesity, fatty liver, liver fibrosis, hepatic sclerosis, hepatic injury, cholestasia, gall stone,
Curative effect in the diseases such as angiocardiopathy, atherosclerosis.
Creative and novelty：
Have no any related Vidofludimus in treatment diabetes, obesity, fatty liver, angiocardiopathy, liver so far
The report applied in the drug of the diseases such as hardening, hyperglycemia, hepatic injury.Therefore the Vidofludimus that the present invention provides is at these
Have the function for the treatment of in terms of disease, is all the new function about Vidofludimus, it is creative and innovative.
Practicability：
Hyperglycemia, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, fatty liver, liver fibrosis, liver are hard
The diseases such as change, hepatic injury, cholestasia, gall stone, angiocardiopathy, atherosclerosis seriously affect health and the life of the mankind
Life, therefore, practical work(of this Vidofludimus that the present invention provides in terms of preparing the pharmaceutical preparation for treating these diseases
Can, there is important social value and huge economic value, there is practicability.
In some embodiments, the compound in the method for the invention can be configured to pharmaceutical composition in some administrations
It is applied in scheme.The composition of drug of the present invention may include that available salt or drug administration carrier is administered in the combound itself and its.
Such composition is also selectively included other therapeutic agents.
" drug administration carrier " word, which refers to, can be used for patient together with the compounds of this invention and not destroy the nothing of its pharmacological activity
Cytotoxic drug carrier.Available drug administration carrier in aforementioned pharmaceutical compositions includes but not limited to：Ion-exchanger, aluminium oxide are stearic
Sour aluminium, lecithin, haemocyanin such as human serum albumins, buffer medium such as phosphate, glycine, sorbic acid, potassium sorbate are satisfied
With the partial glyceride mixtures of vegetable fatty acid, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid hydrogen
Potassium, sodium chloride, zinc salt, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose preparation, polyethylene glycol, carboxylic first
Base sodium cellulosate, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, lanolin and self-emulsifying drug delivery systems
Such as alpha tocopherol, cetomacrogol 1000 succinate or other similar Polymeric delivery patterns.
" metabolic disease " used in the present invention refers to and is metabolized relevant any disease or disorders.For example, metabolic disease
Including but not limited to：Hyperglycemia, insulin resistance, hyperlipidemia, Hypercholesterolemia, diabetes, obesity, Metabolic syndrome
Sign, metabolic disorder and relevant disease, the disease (liver disease) of liver, Fatty Liver Disease (hepatic steatosis), non-alcoholic fat
Fat liver disease, hepatic sclerosis, liver fibrosis, chronic and acute liver failure, biliary cirrhosis, primary sclerotic bile duct
The total hair disease of inflammation, cholestasis, cholelith atherosclerosis and above-mentioned disease.
In certain pharmaceutical compositions only using compound described herein as its active constituent, medication can also wrap
It includes and the subject is treated with other medicaments or therapy.Such agent treatment includes but not limited to：Anemia is controlled
It treats, diabetotherapy, hypertension therapeutic, cholesterol therapy, neurologic agent, adjusts the drug of cardiovascular function, adjust haemocyte
The drug of generation；Hormone and antagonist influence gastrointestinal function, the chemotherapeutic agent of microbial diseases and/or tumor disease
Chemotherapy.
Certain medicaments or therapy can carry out administering drug combinations with compound of the present invention, as matrix metalloproteinase inhibits
Agent, lipoxidase inhibitor, cytokine antagonist, immunosuppressor, cell factor, growth factor, immunomodulator, forefront
Parathyrine or anti-angiogenic antihyperproliferative compound.
It with the compounds of this invention is same that term used herein " combination " and its relative words were corresponding in turn to, which is therapeutic agent,
When or in order apply.For example, certain described compound can be simultaneously or sequentially with another therapeutic agent in single unit dosage forms
Using.Therefore, the present invention provides a kind of single unit dosage forms, including the compound, a kind of additional therapeutic agent.It is given in many
In prescription case, when patient or individual simultaneously be exposed to two or more medicaments when, if patient or individual in some particular target group
It knits or sample (for example, in brain, in serum etc.) while the associated treatment effect for showing agents useful for same, it is generally recognized that they are
It is played a role in the form of " combination ".
It can use salt product, that salt used that should preferentially come from nothing if these change the pharmacy that composition is the compounds of this invention
Machine or organic bronsted lowry acids and bases bronsted lowry.Alkali salt includes ammonium salt, alkali metal salt (such as calcium, sodium, magnesium and sylvite), alkali salt (such as calcium and magnesium salts)
With organic alkali salt (as dicyclohexyl amine salt, N- methyl-D-glucamine salts or with amino acid such as arginine, lysine
Salt).Ackd salt includes：Acetate, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate,
Butyrate, citrate, camphor hydrochlorate, camsilate, pentamethylene, digluconate, lauryl sulfate, ethanesulfonic acid
Salt, fumarate, gluceptate, glycerophosphate, Hemisulphate, heptan, caproate, hydrochloride, hydrobromate, hydroiodic acid
Salt, 2- isethionates, lactate, maleate, mesylate, 2- naphthalene sulfonates, nicotinate, oxalates, pamoic acid
Salt, pectate, persulfate, 3- phenylpropionic acids salt, picrate, Pivalate, propionate, succinate, tartrate,
Thiocyanic acid, toluene fulfonate and undecylate.
Compound composition of the present invention may also include, preparation needed for dependence, pharmaceutical non-toxic carrier or dilution
Agent.Usually it is defined as the medium for preparing animal or the pharmaceutical composition of people.Suitable diluent should be selected to not
Influence the biological activity of composition.Such diluent has：Distilled water, physiological phosphate buffer salt solution, Ringer's solution, Portugal
Grape sugar juice and HankShi solution.In addition, pharmaceutical composition or preparation may also include other carriers, adjuvant or nontoxic non-control
The stabilizer etc. of the property treated non-immunogenic.
Compound composition of the present invention may also include, wetting agent, emulsifier and lubricant, such as lauryl sodium sulfate
And magnesium stearate and colorant, releasing agent, coating agent, sweetener, flavoring agent and aromatic, preservative and antioxidant
It may be present in composition.Pharmaceutical antioxidant includes：Water soluble antioxidant, as ascorbic acid, cysteine hydrochloride,
Niter cake, sodium pyrosulfite, sodium sulfite etc.；Oil-soluble inhibitor, such as ascorbyl palmitate, Butylated hydroxy benzene
Methyl ether (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol etc.；And metal-chelator, as citric acid,
Ethylenediamine tetra-acetic acid (EDTA), sorbierite, tartaric acid, phosphoric acid etc..
The pharmaceutical composition of the present invention can be configured to the form of solid or liquid.Including following suitable form of medication：(1)
Oral medication, such as filled medicament (aqueous or non-aqueous solution or suspension), tablet, cheek, sublingual and systemic Absorption agent, bolus,
Powder, granule, sublingual paste；(2) parenteral administration is prepared as sterile solution or suspension or sustained release agent, leads to
Cross subcutaneous, intramuscular, intravenous or epidural injection；(3) topical application, such as emulsifiable paste, ointment, for releasing for skin, lung or oral cavity
Put controlled patch or spray；(4) drop rectum with drug is such as used as emulsion or foam；(5) other：Sublingual administration, it is ophthalmically acceptable, percutaneously
Or intranasal, lung and the intake of other mucous membranes.
The preparation method of the pharmaceutical composition of the compound include with arbitrary process by the compounds of this invention and carrier or
A variety of auxiliary element combinations.It under normal conditions, can be by the compounds of this invention and carrier (liquid-carrier, subdivided solids carrier or two
Person has) uniformly and intimately combination preparation, and as needed by product figuration.
It, can be by slowing down drug from the speed of slow trapping is subcutaneously or intramuscularly noted to extend drug effect in certain situations.It can lead to
The liquid suspension of the crystallization or amorphous substance that prepare poorly water-soluble is crossed to realize this purpose.The absorption rate of drug depends on
In its solution rate, rate of dissolution is likely to be dependent on crystal size and crystal form again.Alternatively, by dissolving or hanging drug
Float in oiliness carrier to postpone parenteral absorption.
It can be by by biodegradable polymer (such as polylactide-polyglycolide) in the compound and microencapsule matrices
In conjunction with its injectable drug depot dosage form is made.It, can according to the property of the ratio and particular polymers used of drug and polymer
The rate of Drug controlled release.Other biodegradable polymers include polyorthoester and polyanhydride.It also can be by by drug
It is embedded in liposome or micro emulsion, to prepare the injectable drug depot dosage form compatible with bodily tissue.
The drug ingedient of the present invention can arbitrarily take orally acceptable dosage form oral medication, and dosage form includes but not limited to：Capsule,
Tablet and water slurry and solution.For oral tablet, common coating has lactose and cornstarch, usually can also
Lubricant, such as magnesium stearate is added.For oral capsule preparation, available diluent includes that lactose and dry corn form sediment
Powder.When with water slurry and the oral medication of solution and formulation propylene glycol, active constituents of medicine is combined with emulsifier and suspending agent.
If it is desired, certain sweeteners and/or flavoring agent and/or colorant can be added.
The dosage form for the suitable oral medication that the present invention describes can be capsule, and cachet, pill, tablet, pastille is (usually
Use sucrose and Arabic gum or bassora gum as flavor ameliorating substances), pulvis, granule, or be dissolved in aqueous or non-aqueous liquid and making
(make at solution or suspension, or as Water-In-Oil or oil-in-water liquid emulsion, or as elixir or syrup, or as pastille
With inert base, such as gelatin and glycerine or sucrose and Arabic gum) and/or mode of gargling.Various dosage forms contain predetermined amount
The compounds of this invention is as one of its active constituent.Compound of the present invention can also bolus, electuary or paste make
With.
The liquid dosage form of the compounds of this invention oral medication includes pharmaceutical emulsion, microemulsion, solution, suspension, sugar
Slurry and elixir.In addition to the active ingredient (s, liquid dosage form also contains usually used inert diluent in the art, such as water or
Other solvents, solubilizer and emulsifier, such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate alcohol, benzylalcohol, Ergol, third
Glycol, 1,3 butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame
Oil), glycerine, tetrahydrofuran alcohol, polyethylene glycol and aliphatic ester D-sorbite and their mixture.
When the pharmaceutical composition of the present invention is more easy to work to targeted treatment area or organ by local application, you can choosing
Select this administering mode.In order to be locally applied to skin, active component can be suspended or dissolved in drug administration carrier, then by this medicine
Compositions are configured to ointment.The local administration carrier of the compounds of this invention includes but not limited to：Mineral oil, liquid petroleum,
White oil, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, reactive compound can be suspended or be dissolved
Lotion or creme appropriate is made in carrier, then by the pharmaceutical composition, this kind of carrier includes but not limited to：Mineral oil takes off
Water sorbitol monostearate, polysorbate60, cetyl, cetostearyl alcohol, 2- octyldodecanols, benzyl alcohol and water.
The pharmaceutical composition of the present invention can also be applied topically to lower intestinal tract by the way that rectal suppository or enema agent appropriate is made.The present invention
Further include that compound is prepared into local administration transdermal patch.
It can be by the way that aerosol or inhalant administration be made in the drug ingedient of the present invention.Such medicament can match according to pharmacy
In square field prepared by widely applied technology, is also prepared as saline solution.This kind of prior art is often used benzylalcohol or other
Preservative, fluorocarbon and/or other solubilizer or dispersant, sorbefacient appropriate are to improve its bioavailability.
The additional advantage of transdermal patch is the controlled delivery for realizing the compounds of this invention to body.The compound can be dissolved
Or it is dispersed in medium appropriate and makes this dosage form.Absorption of the skin to compound can be increased with absorption enhancer.Also may be used
The mode being scattered in by using rate controlling membranes or by compound in polymer substrate or gel realizes that compound passes through skin
The control of skin rate.
Description of the drawings
In all attached drawings, Vidofludimus is labeled as Vido, and the calcium salt of Vidofludimus terminal carboxyl groups is got the bid in figure
Vido- calcium salts are denoted as, it is sodium salt that the sodium salt of terminal carboxyl group marks in figure.In all embodiments at control group and drug
Difference between reason group is analyzed with student ' s t-test.* indicates that the significant difference of opposite blank control is analyzed in figure,
Wherein * indicates p<0.05, * * indicates p<0.01, * * * indicate p<0.001.
Fig. 1, which is Vidofludimus and its calcium salt and sodium salt, can reduce ob/ob mouse livers/percent weight.
Fig. 2, which is Vidofludimus and its calcium salt and sodium salt, can reduce ob/ob mouse liver total cholesterol levels.
Fig. 3, which is Vidofludimus and its calcium salt and sodium salt, can reduce ob/ob mouse liver triglyceride levels.
Fig. 4, which is Vidofludimus and its calcium salt and sodium salt, can reduce ob/ob mice serum total cholesterol levels.
Fig. 5, which is Vidofludimus and its calcium salt and sodium salt, can reduce ob/ob mice serum triglyceride levels.
Fig. 6 is that liver section HE dyeing shows that Vidofludimus and its calcium salt and sodium salt can reduce ob/ob mouse livers
Fat bubble.
Fig. 7 is that the dyeing of liver section oil red shows that Vidofludimus and its calcium salt and sodium salt can reduce ob/ob Mouse Livers
Dirty Fat Accumulation.
Fig. 8, which is Vidofludimus and its calcium salt and sodium salt, can reduce db/db mouse livers/percent weight.
Fig. 9, which is Vidofludimus and its calcium salt and sodium salt, can reduce db/db mouse liver triglyceride levels.
Figure 10, which is Vidofludimus and its calcium salt and sodium salt, can reduce db/db mouse liver total cholesterol levels.
Figure 11, which is Vidofludimus and its calcium salt and sodium salt, can reduce db/db mice serum total cholesterol levels.
Figure 12, which is Vidofludimus and its calcium salt and sodium salt, can reduce db/db mouse blood sugar levels.
Figure 13 is that liver section HE dyeing shows that Vidofludimus and its calcium salt and sodium salt can reduce db/db mouse livers
Fat bubble.
Figure 14 is that the dyeing of liver section oil red shows that Vidofludimus and its calcium salt and sodium salt can reduce db/db Mouse Livers
Dirty Fat Accumulation.
Figure 15 is Vidofludimus and its calcium salt and sodium salt can reduce the AST in the mice serums of APAP induced liver injuries
With ALT levels.
Figure 16 is Vidofludimus and its calcium salt and sodium salt can reduce ALP water in the mice serums of APAP induced liver injuries
It is flat.
Figure 17 is that liver section HE dyeing shows that Vidofludimus and its calcium salt and sodium salt can protect and repair APAP and lure
The hepatic injury led.
Figure 18 be Vidofludimus and its calcium salt and sodium salt to lower collagen gene, up-regulation cholic acid cycle relevant
FXR expression of target gene is horizontal.
Figure 19 is that Vidofludimus and its calcium salt and sodium salt can induce nuclear receptor FXR and co-activator SRC2 and SRC3
In conjunction with.
Specific implementation mode
Following embodiment will the present invention is further illustrated in conjunction with attached drawing.
Embodiment one：Curative effects of the Vidofludimus in obesity mouse.
Test method：The ob/ob mouse (family name B6/JNju-Lepem1Cd25/Nju) that this experiment uses are fat
Disease mouse model.With fat, blood fat is high, adipocyte increases the symptoms such as increase.It is small with the male ob/ob of 11 week old or so
Mouse is fed, free water in Xiamen University's Experimental Animal Center SPF rank animal houses with conventional feed.During experiment, mouse
It is fed with high lipid food (Research Diets, D12492).Drug used is respectively Vidofludimus, Vidofludimus
The structural formula difference of the calcium salt of terminal carboxyl group or the sodium salt of terminal carboxyl group, the calcium salt and sodium salt is as follows：
Compound DMSO high concentrations dissolve, then are matched with 40%HBC (2-hydroxypropyl- β-cyclodextrin)
It is set to working concentration, makes DMSO a concentration of 10%, and makes the working concentration of 100 μ l solution final compounds of intraperitoneal injection be
10mg/kg (drug/mouse weight).Blank control group is directly diluted in 40%HBC solution with the DMSO of equivalent.Every morning 9
Point injection, once a day.Injection compound fasting 16h after the 10th day, eyeball takes blood to collect mice serum, for detecting in serum
The index of correlation of glycolipid metabolism includes the level of serum cholesterol and triglycerides, builds up bioengineering according to Nanjing respectively and grinds
Study carefully total cholesterol (TCHO) testing cassete and triglycerides (TG) assay kit be detected.Murine liver tissue is collected, is taken
Partial liver tissue is fixed with paraformaldehyde, carries out embedding paraffin according to a conventional method, cuts out the slice of 5 microns of thickness, routine side
Method HE dyeing.Portion of tissue frozen section is taken, is dyed for oil red.Partial liver tissue is homogenized, and bioengineering is built up with Nanjing
Research institute triglycerides (TG) assay kit and total cholesterol (TC) assay kit detection liver organization triglycerides and
Total cholesterol level.
Oil red colouring method：Liver organization is rapidly frozen in isopentane in liquid nitrogen, embedded optimized cutting temperature,
It is cut on cryostat.Oil red fuel formulations：0.5g oil red O, isopropanol (98% or more content) 100ml, for 24 hours 60 DEG C of bakings
In case, fully storing liquid is used as after dissolving.Face the used time take dyeing stoste 6ml, add distilled water 4ml, dilute, stand 5~10min after
Filtering, this liquid are preserved no more than 1~2h.
Colouring method：
(1) frozen section 10um is thick, and 10% paraformaldehyde is washed after fixing 10~15min；
(2) it is placed in the oil red dye liquor 5h of sealing container splendid attire；
(3) with 60% ethyl alcohol color separation, it is red to impregnate slice to cytoplasm, until background color is white；
(4) it washes, 37 DEG C of 5min；
(5) 10~20s of the light dye core of hematoxylin；Water or 1% phosphoric acid hydrogen dimethylamino, which rinse, becomes blue；
(7) glycerine mixes water seal piece.As a result judge：Fat takes on a red color, and karyon is in blue.
Difference in all embodiments between control group and drug-treated group is analyzed with student ' s t-test.
Test result：Compared to blank control, the ob/ob mouse livers/body of Vidofludimus or its calcium salt, sodium salt processing
Again than being significantly lower than control group (Fig. 1).The mouse liver total cholesterol (Fig. 2) of Vidofludimus or its calcium salt, sodium salt processing
It is horizontal significantly lower than control group with liver tg (Fig. 3).The mice serum of Vidofludimus or its calcium salt, sodium salt processing
Total cholesterol (Fig. 4) and serum triglyceride (Fig. 5) are horizontal significantly lower than blank control group.
Nonalcoholic fatty liver is a kind of no excessive drinking history, fat accumulation in the liver cell caused by a variety of causes, with
Diffusivity liver cell Macrovesicular steatosis and the clinical pathology syndrome that accumulation of lipid is main feature, it is considered to be metabolism is comprehensive
A kind of pathological manifestations of the simulator sickness in liver.Liver tissue slices HE coloration results show that liver cell occurs apparent in control group
Fat vacuole, and the fat bubble of mouse liver cell of Vidofludimus or its calcium salt, sodium salt processing significantly improves (figure
6).Oil red O be lipid-soluble dye, in fat can high dissolution, can specificity make the neutral fats such as triglycerides in tissue
Coloring.In daily pathological diagnosis and research work, show that the fat in tissue is dyed frequently with oil red O.In order into one
Step proves that the vacuole in the picture of liver section HE dyeing is exactly the aggregation of the neutral fats such as triglycerides, we are contaminated with oil red again
Color analyzes liver section.The result shows that the fat particles of numerous big drops are shown in the liver section of control group, and
Significantly less than control group, fat contains olesome in the mouse liver slice that Vidofludimus or its calcium salt, sodium salt are handled
For amount considerably less than control group (Fig. 7), the result is consistent with the result that HE is dyed, and shows Vidofludimus and its calcium salt, sodium salt
There is good curative effect to fatty liver.
Conclusion：Hyperlipemia includes hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia
(Hypertriglyceridemia) and all high plyability hyperlipemia of the two.This example demonstrates that Vidofludimus and
Its calcium salt, sodium salt are in metabolics diseases such as treatment hypertriglyceridemia, hypercholesterolemia, hyperlipemia, fatty liver, obesity
Sick aspect has good efficacy.
As described in this specification technical background, the level of total cholesterol and triglycerides is excessively high in blood, is cardiovascular disease
The Warning Index of disease, the excessively high risk for reflecting that body suffers from angiocardiopathy of these index levels are high.Therefore in the present embodiment
Vidofludimus and its calcium salt, sodium salt processing mouse can significantly lower serum total cholesterol and blood triglyceride levels, show
Vidofludimus and its calcium salt, sodium salt have therapeutic effect in angiocardiopathy.
As described in this specification technical background, high total cholesterol is with carotid artery atherosclerosis plaques lesion degree at positive
It closes.Therefore, Vidofludimus and its calcium salt, sodium salt processing mouse can effectively reduce serum total cholesterol water in the present embodiment
It is flat, show that Vidofludimus and its calcium salt, sodium salt have curative effect to atherosclerosis.
As described in this specification technical background, hypercholesterolemia, hypertriglyceridemia, liver fat accumulation are also generation
Thank syndrome, metabolic disturbance diseases, the disease (liver disease) of liver, Fatty Liver Disease (hepatic steatosis), non-alcoholic fat
The performance of fat liver disease, and liver fibrosis, hepatic sclerosis and chronic liver failure can be caused.Therefore, the present embodiment experimental result
Show Vidofludimus and its calcium salt, sodium salt metabolic syndrome, metabolic disorder relevant disease, liver disease (liver disease
Disease), Fatty Liver Disease (hepatic steatosis), nonalcoholic fatty liver disease, hepatic sclerosis, liver fibrosis, chronic liver function decline
Exhaust and the total hair disease of above-mentioned disease in curative effect.
Embodiment two：Curative effects of the Vidofludimus in db/db disease mices.
Test method：Db/db mouse (the family name BKS.Cg-Dock7 that the present embodiment usesm+/+Leprdb/JNju)
Belong to type II diabetes model, animal started voracity at one month and gets fat, and then generated symptoms, hyperlipidemia and the fat such as hyperglycemia
Fat liver is also the complication of the disease model.The present embodiment is existed using Research of Animal Model for Study Vidofludimus and its salt product
Treat the effect in terms of metabolic disease.
Utilize the male db/db mouse for 11 week old that high lipid food (Research Diets, D12492) is fed, abdominal cavity note
The Vidofludimus and its calcium salt, sodium salt solution that the method as described in embodiment one is equipped with are penetrated, 100 μ l chemical combination of intraperitoneal injection is made
The final working concentration of object solution is 10mg/kg (drug/mouse weight).Blank control group is directly diluted in the DMSO of equivalent
40%HBC solution.9 points of injections of every morning, once a day.Injection compound fasting 16h after the 10th day cuts the German shellfish of rat-tail
Bright (B/BRAUN) good blood glucose meter and Bei Lang times of good blood sugar test paper survey blood glucose again.Then eyeball takes blood to collect mice serum, for examining
Survey total cholesterol level in serum, detection method such as embodiment one.Murine liver tissue is collected, partial liver tissue poly first is taken
Aldehyde is fixed, and carries out embedding paraffin according to a conventional method, cuts out the slice of 5 microns of thickness, conventional method HE dyeing.Take portion of tissue ice
Freeze slice, is dyed for oil red.Partial liver tissue is homogenized, and liver organization triglycerides and total courage are detected by one method of embodiment
Sterol levels.
Test result：Compared to blank control, the db/db mouse livers/body of Vidofludimus or its calcium salt, sodium salt processing
Again than being significantly lower than control group (Fig. 8).The mouse liver triglycerides (Fig. 9) of Vidofludimus or its calcium salt, sodium salt processing
It is horizontal significantly lower than control group with total cholesterol of liver (Figure 10).The mouse blood of Vidofludimus or its calcium salt, sodium salt processing
Clear total cholesterol (Figure 11) and blood glucose (Figure 12) are horizontal significantly lower than blank control group.
Liver tissue slices HE coloration results show that apparent fat vacuole occurs in liver cell in control group, and
The fat bubble for the mouse liver cell that Vidofludimus or its calcium salt, sodium salt are handled significantly improves (Figure 13).In order to further
Prove that the vacuole in the picture of liver section HE dyeing is exactly the aggregation of the neutral fats such as triglycerides, we are dyed with oil red again
Liver section is analyzed.The result shows that the fat particles of numerous big drops are shown in the liver section of control group, and
Significantly less than control group, fat contains olesome in the mouse liver slice that Vidofludimus or its calcium salt, sodium salt are handled
For amount considerably less than control group (Figure 14), the result is consistent with the result that HE is dyed, and shows Vidofludimus and its calcium salt, sodium salt
There is good curative effect to fatty liver.
Conclusion：This example demonstrates that Vidofludimus and its calcium salt, sodium salt are in treatment hyperglycemia, hypercholesteremia
There is good efficacy in terms of the metabolic diseases such as disease, hyperlipemia, fatty liver, diabetes, obesity.
As described in this specification technical background, the level of Blood Glucose and total cholesterol is excessively high, is angiocardiopathy
Warning Index, the excessively high risk for reflecting that body suffers from angiocardiopathy of these index levels are high.Therefore in the present embodiment
Vidofludimus and its calcium salt, sodium salt processing mouse can significantly lower blood glucose, serum total cholesterol and blood triglyceride levels,
Show that Vidofludimus and its calcium salt, sodium salt have therapeutic effect in angiocardiopathy.
As described in this specification technical background, high total cholesterol is with carotid artery atherosclerosis plaques lesion degree at positive
It closes.Therefore, Vidofludimus and its calcium salt, sodium salt processing mouse can effectively reduce serum total cholesterol water in the present embodiment
It is flat, show that Vidofludimus and its calcium salt, sodium salt have curative effect to atherosclerosis.
As described in this specification technical background, hyperglycemia, hypercholesterolemia, liver fat accumulation are also Metabolic syndrome
Sign, metabolic disturbance diseases, the disease (liver disease) of liver, Fatty Liver Disease (hepatic steatosis), nonalcoholic fatty liver disease
The performance of disease, and liver fibrosis, hepatic sclerosis and chronic liver failure can be caused.Therefore, the present embodiment the experimental results showed that
Vidofludimus and its calcium salt, sodium salt are in metabolic syndrome, metabolic disorder relevant disease, the disease (liver disease) of liver, fat
Fat liver disease (hepatic steatosis), nonalcoholic fatty liver disease, hepatic sclerosis, liver fibrosis, chronic liver failure and
Curative effect in the total hair disease of above-mentioned disease.
Embodiment three：The liver protecting of Vidofludimus and the function in terms of reparation.
Test method：It is that research is protected that excessive use paracetamol (APAP), which causes chmice acute liver lesion induced by drugs wound model,
One of common model of liver drug, APAP are the Typical Representative objects for causing drug induced hepatic injury by active oxygen or active nitrogen.
APAP, which is excessively used, can cause liver active oxygen to increase, glutamic-oxalacetic transaminease AST, glutamic-pyruvic transaminase ALT and alkaline phosphatase etc.
Activity rises, and causes liver organization downright bad.The present embodiment uses model inspection Vidofludimus and its salt product pair
The protection of APAP induced synthesis hepatic injuries and repair function.
With the C57B6/J wild-type mices of 17 week old, in Xiamen University's Experimental Animal Center SPF rank animal houses, with normal
Advise forage feed, free water.Vidofludimus and its calcium salt and sodium salt such as embodiment one configure, and make 100 μ l of intraperitoneal injection
The final working concentration of compound solution is 10mg/kg (drug/mouse weight).Blank control group directly uses the DMSO of equivalent to dilute
In 40%HBC solution.9 points of injections of every morning after injecting 5 days, gave mouse to inject in the 5th day at 3 points in the afternoon once a day
500mg/kg (drug/mouse weight) APAP that PBS fresh lysates are prepared.It puts to death mouse afterwards for 24 hours, partial liver tissue is taken to use
Paraformaldehyde is fixed, paraffin embedding, slice, HE dyeing.Partial liver tissue liquid nitrogen cryopreservation, Trizol reagents extract RNA, reversion
After recording into cDNA, carried out in real time with RealMasterMix (SYBR Green I) kit of Tiangeng biochemical technology Co., Ltd
Quantitative fluorescent PCR reacts, expression of the related gene with respect to actin genes in detection liver organization.Serum is taken, for detecting
Glutamic-oxalacetic transaminease AST, glutamic-pyruvic transaminase ALT and alkaline phosphatase are horizontal in serum.Control group and drug in all embodiments
Difference between processing group is analyzed with student ' s t-test.
Test result：Compared with blank control group, the mice serum of Vidofludimus or its calcium salt or sodium salt has been injected
Middle AST and ALT horizontal (such as Figure 15) and ALP horizontal (Figure 16) are substantially less than blank control group.Mouse liver is sliced HE dyeing knots
Fruit such as Figure 17, the visible lobuli hepatis inner cell infiltration of blank control group pathological section is apparent, is in empty balloon-shaped and necrosis region, in leaflet and
Portal area has that cell is muddy, karyopycnosis or has dissolved broken, and hepatic cell cords is fuzzy, and hepatic injury is serious.Compared to blank control,
Vidofludimus or the mouse liver of its calcium salt or sodium salt processing are clearly better (Figure 17) by the APAP damages induced.Compared to sky
Collagen gene α 1 (I) in white control, Vidofludimus or its calcium salt or the mouse liver tissue of sodium salt processing
Collagen and α 2 (I) collagen expression is lowered；Cholic acid recycles relevant FXR target genes BSEP and OST alpha expression level up-regulation
(Figure 18).
Conclusion：This example demonstrates that Vidofludimus and its esters energy maintenance hepatic injury, improvement liver function, in treatment liver
There is protection and repair function well in terms of damage.
As described in this specification technical background, the result of hepatic injury frequently can lead to hepatonecrosis, fatty liver, cholestasis,
Liver fibrosis, hepatic sclerosis etc., fibrosis therein, the i.e. over-deposit and abnormal distribution of each ingredient of liver cell epimatrix.Glue
Former proteinosis is one of typical feature, and the expression for detecting collagen gene can be as liver fibrosis, the index of hepatic sclerosis
One of.One of the reason of biliary cycle obstacle is also cholestasis, biliary cirrhosis, hepatic injury.The present embodiment the result shows that
Collagen gene expression declines in the mouse liver that Vidofludimus or its esters are handled, and promotes cholic acid cycle related
It is hard in hepatonecrosis, fatty liver, cholestasis, liver fibrosis, liver to also show Vidofludimus and its esters for gene expression
Change, cholelith artery sclerosis and altogether send out disease in treatment function.
Example IV：Identify that Vidofludimus is the ligand of nuclear receptor FXR.
Test method 1：AlphaScreen(Amplified Luminescent Proximity Homogenous
Assay) analysis method is a kind of biochemical analysis method of very sensitive energy detection compound interaction of PE companies invention.
The brief principle of this method is：With the counselor work polypeptide of biotin labeling, can be marked with Streptavidin's
Donor bead combines；It, can be with ligand binding domains (LBD) albumen of the FXR marked with hexahistine His6
The receptor pearl for being marked with nickel combines.It changes if be added has ligand compound to can induce FXR conformations in the reaction system
To make it be combined with counselor work polypeptide, at this moment donor bead and receptor pearl are close, are excited with 680nm light, Jiu Huijian
Measure 520-620nm fluorescence signals.The reaction concrete operations according to Perkins-Elmer companies Alpha Screen
Nickel chelate detection kit kits carry out, and the Envision of Perkins-Elmer companies is used after reaction
Xcite Multilabel Reader microplate reader is read.
The mechanism of action of nuclear receptor is that occurred conformation changes by interacting with ligand, to swash with numerous different auxiliaries
Selecting predictors living are in conjunction with the coordinated expression for carrying out controlling gene.SRC2 and SRC3 is the typical nuclear receptor coactivity factor 1 of two of which
Son.The present embodiment raises auxiliary adjusting by Alphascreen analysis methods, to detect ligand compound induced nuclear receptor FXR
The binding ability of factor S RC2 and SRC3.The reaction system of the experiment is the FXR receptor LBD eggs of the fusion histidine tag of 20nM
In vain, the SRC2-3 (polypeptide of motif containing LXXLL that third nuclear receptor combines in SRC2) or SRC3-3 of 20nM biotinylations label
(polypeptide of motif containing LXXLL that third nuclear receptor combines in SRC3) co-factor polypeptide, the donor and receptor pearl of 5 μ g/ml delay
Fliud flushing (50mM MOPS, 50mM NaF, 0.05mM CHAPS, and 0.1mg/ml bovine serum albumin,
PH7.4), the Vidofludimus of 5 μM of working concentrations of addition or its calcium salt or sodium salt, the rooms in 384 orifice plates 50 μ L of reaction system
The transmitting optical signal of 520~620nm under 680nm exciting lights is read after temperature reaction 1h with AlphaScreen detectors.SRC2-3 and
SRC3-3 sequences difference is as follows：SRC2‐3,QEPVSPKKKENALLRYLLDKDDTKD；SRC3‐3,
PDAASKHKQLSELLRGGSG.Blank control is the ligand compound replaced with isometric DMSO in experimental group.
Test result：Compared to blank control group, adds and detected in the reaction of Vidofludimus or its calcium salt or sodium salt
To the fluorescence signal (Figure 19) significantly improved.AlphaScreen identifies that the compound of Vidofludimus and its salt form can lure
FXR is led to be combined with co-factor.It is real by target protein FXR to the effect of relevant disease that Vidofludimus is demonstrated from mechanism
Existing.
Test method and result 2：As described in above-described embodiment three, fluorescent quantitative PCR result is shown, Vidofludimus or
Its calcium salt or sodium salt processing can raise the expression (Figure 18) of target gene BSEP and the OST α of FXR, it is shown that
The adjustment effect of Vidofludimus or its calcium salt or sodium salt to FXR transcriptional activities.Further illustrate that Vidofludimus is energy
Adjust the ligand of FXR transcriptional activities.
Conclusion：The compound induced nuclear receptor FXR of Vidofludimus and its salt form is combined with co-activator, on energy
The expression for adjusting FXR target genes in liver, shows that Vidofludimus is the ligand of FXR.Show Vidofludimus and its salt shape
The compound of formula can have in FXR mediates the various physiology adjusted, the relevant disease of pathology by activating FXR and adjust work(
Can, including hyperglycemia, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, fatty liver, hepatic sclerosis, hepatic injury,
Kidney trouble, cholestasia, gall stone, angiocardiopathy, atherosclerosis and relevant disease total hair disease.
Claims (10)
1. applications of the compound Vidofludimus in the drug or health products for preparing prevention and treatment metabolic disease.
2. application as described in claim 1, it is characterised in that it is solid that the metabolic disease refers to hyperglycemia, hyperlipemia, high courage
Alcoholemia, hypertriglyceridemia, diabetes, obesity, and angiocardiopathy, Atherosclerosis caused by above-mentioned disease
Change, liver fibrosis, hepatic sclerosis, metabolic syndrome, metabolic disorder and relevant disease total hair disease.
3. application as described in claim 1, it is characterised in that it is solid that the metabolic disease refers to hyperglycemia, hyperlipemia, high courage
Alcoholemia, hypertriglyceridemia, diabetes or obesity, and angiocardiopathy or artery caused by above-mentioned disease are athero-
Hardening.
4. application as described in claim 1, it is characterised in that the metabolic disease refers to disease (liver disease), the fatty liver of liver
Disease (hepatic steatosis), nonalcoholic fatty liver disease, hepatic sclerosis, liver fibrosis, chronic and acute liver failure.
5. application as claimed in claim 4, it is characterised in that the disease of the liver refers to the liver diseases with hepatic injury symptom.
6. application as claimed in claim 4, it is characterised in that for treating the application during transaminase increases.
7. application as described in claim 1, it is characterised in that the metabolic disease refers to biliary cirrhosis, cholestasis, courage
The total hair disease of stone atherosclerosis and relevant disease.
8. application as described in claim 1, it is characterised in that the metabolic disease is the metabolic disease that nuclear receptor FXR is mediated
Disease, including hyperglycemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, fatty liver, liver are hard
Change, hepatic injury, angiocardiopathy, atherosclerosis, cholestasia, gall stone and relevant disease total hair disease.
9. being applied as described in any one in claim 1 to 9, it is characterised in that Vidofludimus can be that pharmacy can
Salt product.
10. application as claimed in claim 9, it is characterised in that Vidofludimus can exist with sodium salt or calcium salt forms.
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| CN115381800A (en) * | 2022-07-05 | 2022-11-25 | 中国科学院生态环境研究中心 | Selective agonist for liver X receptor and application |
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| CN103038210A (en) * | 2010-07-01 | 2013-04-10 | 4Sc股份有限公司 | Novel calcium salts of compound as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103038210A (en) * | 2010-07-01 | 2013-04-10 | 4Sc股份有限公司 | Novel calcium salts of compound as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
| CN103097338A (en) * | 2010-07-01 | 2013-05-08 | 4Sc股份有限公司 | Novel salts as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110251498A (en) * | 2018-03-12 | 2019-09-20 | 厦门大学 | One kind adjusts active compound of Farnesoid X receptor and application thereof |
| CN115381800A (en) * | 2022-07-05 | 2022-11-25 | 中国科学院生态环境研究中心 | Selective agonist for liver X receptor and application |
| CN115381800B (en) * | 2022-07-05 | 2023-08-25 | 中国科学院生态环境研究中心 | Selective agonist of liver X receptor and application thereof |
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