WO2018230936A1 - NOUVEAU COMPOSÉ PRÉSENTANT UNE DOUBLE ACTIVITÉ PPARα/γ ET COMPOSITION POUR PRÉVENIR OU TRAITER UNE MALADIE MÉTABOLIQUE CONTENANT LEDIT COMPOSÉ EN TANT QUE PRINCIPE ACTIF - Google Patents

NOUVEAU COMPOSÉ PRÉSENTANT UNE DOUBLE ACTIVITÉ PPARα/γ ET COMPOSITION POUR PRÉVENIR OU TRAITER UNE MALADIE MÉTABOLIQUE CONTENANT LEDIT COMPOSÉ EN TANT QUE PRINCIPE ACTIF Download PDF

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WO2018230936A1
WO2018230936A1 PCT/KR2018/006649 KR2018006649W WO2018230936A1 WO 2018230936 A1 WO2018230936 A1 WO 2018230936A1 KR 2018006649 W KR2018006649 W KR 2018006649W WO 2018230936 A1 WO2018230936 A1 WO 2018230936A1
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pparα
compound
formula
preventing
active ingredient
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Korean (ko)
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박상규
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아주대학교산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol

Definitions

  • the present invention relates to a composition for treating metabolic diseases containing a novel compound having a PPAR ⁇ / ⁇ dual action activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Obesity is a disease that causes a variety of diseases, 80% of diabetics, 21% of heart disease patients are caused by obesity, nonalcoholic fatty liver disease is also reported as the main cause of obesity.
  • Non-alcoholic fatty liver disease refers to a disease in which triglycerides accumulate in the liver regardless of drinking, and are known as steatosis and non-alcoholic steatohepatitis (NASH). ) Is included. Simple fatty liver is considered to be a benign disease with a good prognosis, but NASH with inflammation or fibrosis along with fatty liver has been reported as a proliferative disease that causes cirrhosis or liver cancer as a progressive liver disease.
  • Obesity and insulin resistance are risk factors for representative non-alcoholic fatty liver disease. 69-100% of non-alcoholic fatty liver patients are obese, 20-40% of obese patients have non-alcoholic fatty liver, and the prevalence of liver disease among male obese patients is higher than that of female obese. In society, 3-30% of normal weight adults as well as obese patients are reported to have non-alcoholic fatty liver lesions.
  • NAFDL nonalcoholic fatty liver disease
  • the first is to improve the fatty liver by correcting risk factors such as obesity treatment (Zenical), insulin resistance treatment (Metformin, pioglitazone, rosiglitazone), hyperlipidemia treatment (clofibrate, gemfibrozil, bezafibrate, atorvastatin, simvastatin) Drugs that treat and improve it belong here.
  • metformin increases the oxidation of fatty acids, decreases fat-forming enzymes, improves insulinosis and insulin resistance.
  • Chiazolidinedione, rosiglitazone, and pioglitazone activate PPAR ⁇ , a nuclear hormone receptor. Promotes absorption.
  • the second type of treatment is a drug that repairs hepatocellular damage independent of risk factor correction for non-alcoholic fatty liver.
  • Hepatoprotective agents ursodioxycholic acid and taurine
  • antioxidants vitamins E and C
  • nutrition Supplements lecithin, betaine, N-acetylcysteine, etc. belong to this, but to date, there is no ideal drug that is effective in treatment without side effects.
  • the present invention has been confirmed that the problem that the PPAR agonist that has been used as a conventional diabetes treatment for worsening non-alcoholic fatty liver, solve the side effects of the PPAR agonist to exhibit a safe and excellent non-alcoholic fatty liver treatment effect to the human body
  • One compound and a composition for treating metabolic diseases containing the same as an active ingredient are provided.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 may be the same or different, respectively, hydrogen; C1 to C4 alkyl; Any one selected from the group consisting of C1 to C4 alkoxy.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, which comprises the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health food for preventing or improving metabolic diseases containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present invention solves the side effects of the PPAR ⁇ agonist and is excellent in treating non-alcoholic fatty liver and hyperlipidemia.
  • the composition containing the novel compound as an active ingredient can be used as a non-alcoholic fatty liver and hyperlipidemia treatment that can replace the conventional treatment.
  • Figure 2 is a result of identifying the target genes induced expression by PPAR ⁇ and PPAR ⁇ activated in MD001
  • Figure 2A and 2B is a human HA-PPAR ⁇ (A) and HA-PPAR ⁇ (B) expression vector, reporter in HEK293 cells Temporary co-transfection with plasmid (PPRE-pk-Luc) or control reporter plasmid (pk-Luc) and Renilla vector for 24 hours, followed by MD001 (10 ⁇ M), rosiglitazone (rosi (10 ⁇ M) or WY14643 (WY; 10 ⁇ M) Was treated with cells for 24 hours, and luciferase activity was confirmed.
  • FIG. 2C shows the relative expression level of qp-PCR after synthesis of cDNA by treating MD001 (10 ⁇ M) with HepG2 cells for 24 hours, and separating total RNAs.
  • Figure 2D is HepG2 cells transfected with control si-RNA, PPAR ⁇ si-RNA (D) or PPAR ⁇ si-RNA (E) for 48 hours and WY14643 (10 ⁇ M), Treatment with rosiglitazone (10 ⁇ M) or MD001 (10 ⁇ M) for 24 hours followed by cell collection RNA was isolated and qRT-PCR confirmed the relative expression level of the target gene (#, vs. control si-RNA; ⁇ , vs. control si-RNA / vehicle; ⁇ , vs.
  • Figure 3 shows that MD001 induces GLUT expression to promote glucose consumption.
  • HepG2 A
  • differentiated 3T3-L1 adipocytes B
  • differentiated C2C12 root canal cells C
  • MD001 10 , 50 ⁇ M
  • rosi rosiglitazone
  • Figure 4 is a result of confirming the fatty acid oxidation promoting effect by MD001 in vitro
  • Figures 4A, 4B and 4C are HepG2 (A), differentiated 3T3-L1 adipocytes (B) and differentiated C2C12 myotubes (C) Treatment of vehicle or MD001 (10 ⁇ M) for 24 hours, and the total RNA was isolated to synthesize cDNA and qRT-PCR to determine the relative gene expression
  • Figure 4D is HepG2 (D), differentiated 3T3-L1 fat Treatment of cells (E) and differentiated C2C12 root canal cells (F) with vehicle, MD001 (10 ⁇ M) or WY14643 (WY; 10 ⁇ M) for 24 hours, and confirmed the fatty acid oxidation rate, and whether the fatty acid oxidation rate is improved by MD001
  • HepG2 (G), differentiated 3T3-L1 (H), and differentiated C2C12 myotubes (I) were transfected with control or PP
  • WY14643 (WY; 10 ⁇ M) as a positive control for 24 hours
  • FIG. 5 is a result confirming the weight loss caused by MD001 in db / db mice
  • FIG. 6 is a result of confirming the effect of improving the fatty liver by MD001 in db / db mice
  • Figure 6A is ingested vehicle, rosiglitazone (rosi; 20mg / kg) or MD001 (5 or 20mg / kg) for 4 weeks in db / db mice
  • FIG. 6B is liver triglycerol (TG).
  • FIG. 6C is cholesterol
  • FIG. 6D is a result of quantitative analysis of free fatty acid levels.
  • FIG. 6E is performed by qRT-PCR. This is the result of confirming the relative expression level of each gene in db / db mice (*, **, vs. vehicle.The data represent the mean ⁇ SD * P ⁇ 0.01, ** P ⁇ 0.05).
  • FIG. 7 is a result of confirming the effect of reducing the size and macrophage infiltration of fat cells by MD001
  • Figure 7A is a result of performing the H & E staining by collecting the adipose tissue of db / db mice
  • Figure 7B is a high power HPF ( The average number of fat cells per field) is calculated
  • FIG. 7C is a result of confirming relative gene expression by qRT-PCR.
  • FIGS. 7D and 7E are CLS (Crown-like structures) of fat cells in white adipose tissue. (*, **, vs. vehicle; ⁇ , vs. rosi.The data represent the mean ⁇ SD * P ⁇ 0.05, ** P ⁇ 0.01, and ⁇ P ⁇ 0.01).
  • the present invention can provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 may be the same or different, respectively, hydrogen; C1 to C4 alkyl; Alkoxy of C1 to C4; It may be any one selected from the group consisting of halogen.
  • the compound represented by Formula 1 or a pharmaceutically useful salt thereof may be 3-cinnamoyl-5,7-dihydroxy-8-methyl-4-phenyl-2H-chromen-2-one.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be a PPAR ⁇ / ⁇ dual agonist.
  • HEK293 cells are transient for 24 hours with human HA-PPAR ⁇ and HA-PPAR ⁇ expression vectors, reporter plasmids (PPRE-pk-Luc) or control reporter plasmids (pk-Luc) and Renilla vectors.
  • reporter plasmids PPRE-pk-Luc
  • pk-Luc control reporter plasmids
  • Renilla vectors As a result of treatment of the compounds with co-transfected HEK293 cells at 20 ⁇ M for 24 hours and luciferase activity, compound 8a (MD001) simultaneously confirmed the transcriptional activity of PPAR ⁇ and PPAR ⁇ as shown in FIG. 1.
  • the compound represented by Formula 1 may be used as a PPAR ⁇ / ⁇ dual agonist.
  • the present invention can provide a pharmaceutical composition for preventing or treating metabolic diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 or a pharmaceutically useful salt thereof may be 3-cinnamoyl-5,7-dihydroxy-8-methyl-4-phenyl-2H-chromen-2-one, and Formula 1
  • the compound represented by or a pharmaceutically acceptable salt thereof may be a PPAR ⁇ / ⁇ dual agonist.
  • the metabolic disease may be selected from the group consisting of nonalcoholic fatty liver and hyperlipidemia.
  • Peros Peroxisome proliferator-activated receptors
  • PPAR ⁇ Peroxisome proliferator-activated receptors
  • PPAR ⁇ / ⁇ and PPAR ⁇ one of the nuclear hormone receptor family
  • PPAR ⁇ or PPAR ⁇ / ⁇ Activation of PPAR ⁇ or PPAR ⁇ / ⁇ is known to induce the expression of genes that regulate fatty acid oxidation to promote lipid consumption by promoting lipid consumption, whereas PPAR ⁇ induces the expression of lipid carrier genes including adipocyte fatty acid binding protein and CD36.
  • PPAR ⁇ agonists cannot be used to treat fatty liver or hyperlipidemia because they promote lipid production in adipocytes.
  • rosiglitazone a conventional PPAR ⁇ agonist, exacerbated hepatic steatosis, while MD001 was treated, MD001 dose-dependent liver fat.
  • the compound MD001 is found to improve fatty liver, and thus, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be used as a metabolic disease treatment agent.
  • the pharmaceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient is an injection, granules, powders, tablets, pills, capsules, Any formulation selected from the group consisting of suppositories, gels, suspensions, emulsions, drops or solutions may be used.
  • the pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient is a suitable carrier, excipient, disintegrant, sweetener commonly used in the preparation of the pharmaceutical composition. It may further comprise one or more additives selected from the group consisting of coatings, expanding agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants.
  • the carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, capsules.
  • solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like in the composition.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin and the like
  • lubricants such as magnesium styrate and talc may also be used.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • Witsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like may be used as the base material of the suppository.
  • the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, nasal, inhaled, topical, rectal, oral, intraocular or intradermal Via the route can be administered to the subject in a conventional manner.
  • the preferred dosage of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may vary depending on the condition and weight of the subject, the type and severity of the disease, the form of the drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. Can be. According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg. Administration may be administered once a day or divided into several times, thereby not limiting the scope of the invention.
  • the 'subject' may be a mammal including a human, but is not limited thereto.
  • the present invention may be provided as a health food for preventing or improving metabolic diseases containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 or a pharmaceutically useful salt thereof may be 3-cinnamoyl-5,7-dihydroxy-8-methyl-4-phenyl-2H-chromen-2-one, and Formula 1
  • the compound represented by or a pharmaceutically acceptable salt thereof may be a PPAR ⁇ / ⁇ dual agonist.
  • the metabolic disease may be selected from the group consisting of nonalcoholic fatty liver and hyperlipidemia.
  • the health food is used with other foods or food additives in addition to the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
  • the effective dose of the compound contained in the health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range in the case of long-term intake for health and hygiene purposes or health control purposes It is evident that the component can be used in an amount above the range because there is no problem in terms of safety.
  • Methyl phloroglucinol (2.0 g, 14.3 mmol), ethyl benzoyl acetate (g, 28.6 mmol, 2.0 eq.), Trifluoroacetic acid (2 mL) and AcOH (40 mL ) was placed in a round bottom flask and heated for 12 hours to reflux the mixture.
  • Methyl phloroglucinol (4.0 g, 24.6 mmol), ethyl benzoyl acetate (9.90 mL, 57.2 mmol, 2.0 eq.), Trifluoroacetic acid (4 mL) and AcOH (100 mL) were placed in a round bottom flask for 12 hours. After refluxing with heat, the reaction mixture was concentrated under reduced pressure.
  • Acetone was removed under reduced pressure, and the organic layer was separated by dissolving the residue in water (50 mL) / EtOAc (50 mL).
  • the aqueous layer was extracted with EtOAc (50 mL ⁇ 2) and the organic layer was washed twice with water (10 mL ⁇ 2), dried over MgSO 4 , concentrated under reduced pressure and adsorbed onto silica gel.
  • the first reaction compound exhibited high insolubility in a general purification system and was obtained in significantly smaller amounts, so instead of purifying the mixture, the crude mixture was concentrated under reduced pressure and volatiles were removed under high vacuum conditions.
  • the washed organic layer was dried over MgSO 4 and concentrated under reduced pressure.
  • the washed organic layer was dried over MgSO 4 and concentrated under reduced pressure.
  • Acetone was removed under reduced pressure, and the residue was dissolved in water (50 mL) / EtOAc (50 mL) and the organic layer was separated.
  • the cells were maintained at 37 ° C. in a humidification chamber containing 5% CO 2 .
  • HepG2 cells were cultured in minimum Eagle's medium (MEM) medium containing 10% FBS and 1% penicillin and streptomycin.
  • MEM minimum Eagle's medium
  • HEK293, C2C12 and 3T3-L1 cells were maintained in DMEM (Dulbecco's modified Eagle's medium) medium containing 10% FBS and 1% penicillin and streptomycin.
  • DMEM Dulbecco's modified Eagle's medium
  • Plasmid DNA constructs were transfected into cells with polyethyleneimine (EI, Polysciences, Inc., PA, USA) according to the manufacturer's instructions.
  • HA-PPAR ⁇ , HA-PPAR ⁇ , PPRE reporter plasmid (PPRE-pk-Luc) or control reporter plasmid (pk-Luc) and Renilla vector were co-coated for 24 hours.
  • cells were treated with Int B, rosiglitazone (Sigma-Aldrich, USA) or WY14643 (Sigma-Aldrich, USA) at various concentrations for 24 hours.
  • Luciferase activity was confirmed by the Dual-Luciferase Reporter Assay System (Promega, WI, USA), and quantitated according to the manufacturer's protocol using GloMax® (Promega, WI, USA).
  • PPAR ⁇ and PPAR ⁇ targeting si-RNA were transfected into HepG2, 3T3-L1 or C2C12 cells using Lipofectamine 2000 (Invitrogen, USA) for 48 hours.
  • GAPDH was used as an internal control, and primers of the sequences shown in Tables 1 and 2 were used.
  • primer sequence species PPAR ⁇ F 5'-CGGTGACTTATCCTGTGGTCC-3 Human R, 5'-CCGCAGATTCTACATTCGATGTT-3 ' PPAR ⁇ F, 5'-TACTGTCGGTTTCAGAAATGCC-3 ' R, 5'-GTCAGCGGACTCTGGATTCAG-3 ' RXR F, 5'-GACGGAGCTTGTGTCCAAGAT-3 ' R, 5’-AGTCAGGGTTAAAGAGGACGAT-3 ’ ACOX F, 5'-ACTCGCAGCCAGCGTTATG-3 ' R, 5'-AGGGTCAGCGATGCCAAAC-3 ' CPT F, 5'-TCCAGTTGGCTTATCGTGGTG-3 ' R, 5'-TCCAGAGTCCGATTGATTTTTGC-3 ' MLYCD F, 5'-ACGTCCGGGAAATGAATGGG-3 ' R, 5'-GTAACCCGTTCTAGGTTCAGGA-3 ' FATP F, 5'-CTTCGA
  • primer sequence species PPAR ⁇ F 5'-TCTTCACGATGCTGTCCTCCT-3 ' mouse R, 5'-CTATGTTTAGAAGGCCAGGC-3 ' GLUT2 F, 5'-TTCCAGTTCGGCTATGACATCG-3 ' R, 5'-CTGGTGTGACTGTAAGTGGGG-3 ' GK F, 5'-TGAACCTGAGGATTTGTCAGC-3 ' R, 5'-CCATGTGGAGTAACGGATTTCG-3 ' CD36 F, 5'-ATGGGCTGTGATCGGAACTG-3 ' R, 5'-GTCTTCCCAATAAGCATGTCTCC-3 ' LPL F, 5'-TTGCCCTAAGGACCCCTGAA-3 ' R, 5'-TTGAAGTGGCAGTTAGACACAG-3 ' GLUT4 F, 5'-ACACTGGTCCTAGCTGTATTCT-3 ' R, 5'-CCAGCCACGTTGCATTGTA-3 ' ACOX F, 5'-TGTTAAGA
  • fatty acid oxidation analysis cells were cultured with 0.1 mM palmitate (9, 10- [ 3 H] palmitate, 5 ⁇ ci / ml; Perkin Elmer Life, Boston, Mass.) And a-MEM (Hyclone) containing 1% bovine serum albumin. , USA) for 24 hours.
  • the medium was collected, precipitated with 10% trichloroacetic acid (Sigma-Aldrich, USA), mixed vigorously, incubated at room temperature for 20 minutes, and centrifuged at 4 ° C. and 16,000 g for 10 minutes.
  • 10% trichloroacetic acid Sigma-Aldrich, USA
  • the supernatant was transferred to a 1.5 ml tube, placed in a scintillation vial containing 0.5 ml water and incubated at 60 ° C. for 12 hours.
  • radioactivity 3 H 2 O in water was quantified using a liquid scintillation counter (LKB, USA).
  • Interruptin B and rosiglitazone were treated with the cells for 3 days, and the cells cultured in conditioned medium were collected and analyzed for glucose content using Glucose Colorimetric Assay Kit II (BioVision Inc., CA, USA).
  • SPR Surface plasmon resonance
  • Int B was treated at 31.25, 62.5, 125, 250, and 500 ⁇ M concentrations and KD values were determined using the Scrubber 2 program (Informer Technologies, Inc., TX, USA).
  • mice were fasted for 12 hours, sterile glucose (1 g / kg, Sigma-Aldrich, USA) was taken and blood glucose levels were checked at the designated times using OneTouch Ultra (LifeScan Inc., USA).
  • Serum and liver TG, FFA, and total cholesterol were measured using Hitachi clinical analyzer 7180 (HITACHI, JAPAN) and WAKO reagent (WAKO, USA).
  • Serum LDL and HDL contents were measured using SEKISUI reagent (SEKISUI, JAPAN).
  • ALT alanine aminotransferase
  • AST aspartic aminotransferase
  • Tissues such as liver, peripheral adipose tissue, skeletal muscle, spleen, kidney and heart were collected from each group of mice, fixed in 10% formalanine and embedded in paraffin.
  • Tissues cut at 5 ⁇ m were stained with hematoxylin and eosin.
  • the MD001 compound chemically synthesized from the above results was assumed to be bound to PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , and as a result, the compound MD001 binds to PPAR ⁇ and PPAR ⁇ and not to PPAR ⁇ / ⁇ .
  • luciferase activity analysis was performed on HEK293 cells using PPRE.
  • MD001 significantly increased the transcription level through PPAR ⁇ and PPAR ⁇ activity as shown in FIGS. 2A and 2B, whereas the levels of WY14643 and rosiglitazone were lower than MD001.
  • MD001 is an ACOX (acyl-CoA oxidase), CPT (carnitine-palmitoyl transferase), which are PPAR ⁇ target genes related to ⁇ -oxidation in cells that have reduced expression using PPAR ⁇ si-RNA, And increased expression of middlechain acyl-CoA dehydrogenase (mCAD).
  • ACOX acyl-CoA oxidase
  • CPT carnitine-palmitoyl transferase
  • mCAD middlechain acyl-CoA dehydrogenase
  • GPAR glycol kinase
  • CD36 fatty acid binding protein 1
  • FABP1 fatty acid binding protein 1
  • MD001 may be proposed to modulate metabolism through the specific activity of PPAR ⁇ and PPAR ⁇ as dual agents.
  • PPAR ⁇ is recognized as a traditional molecular target for the development of antidiabetic drugs that enhance insulin sensitivity and glucose tolerance.
  • MD001 increased glucose consumption dose-dependently, as shown in Figures 3A, 3B and 3C.
  • quantitative RT-PCR analysis showed that MD001 significantly increased the expression of GLUT2 (HepG2) and GLUT4 (3T3-L1 and C2C12), as shown in FIGS. 3D, 3E and 3F.
  • MD001 like 4A, 4B and 4C, expressed ACOX, CPT, malonyl-CoA decarboxylase (MLYCD) and fatty acid transporter (FATP) in HepG2 and ACOX and CPT expression in 3T3-L1 and C2C12 cells. Increased significantly.
  • MD001 stimulates fatty acid oxidation, as shown in Figure 4D MD001 significantly increased the ⁇ -oxidation rate in HepG2 cells, even in 3T3-L1 and C2C12 root canal cells differentiated as 4E and 4F Similar results were confirmed.
  • MD001 was treated once a day in normal C57BL / 6J mice and diabetic db / db mice.
  • IPGTT intraperitoneal glucose tolerance test
  • FIG. 5B and Supplementary Fig. 3A
  • IPITT insulin tolerance test
  • TZDs including rosiglitazone, pioglitazone and troglitazone, are known to have side effects such as severe weight loss in humans as well as animals, and MD001 has also been a cause of side effects such as weight loss.
  • Rosiglitazone was used as a positive control to confirm the effect of hyperglycemia and lipid profile improvement in db / db mice.
  • MD001 a PPAR ⁇ / ⁇ dual agonist as shown in FIGS. 5D-5E and 5K, significantly reduced blood glucose, triglycerol (TG) and free fatty acids in db / db mice.
  • TG triglycerol
  • MD001 did not affect the levels of plasma lipids and blood glucose compared to the control normal C57BL / 6J mice.
  • rosiglitazone significantly increased alanine transferase (ALT) and aspartate aminotransferase (AST) levels in the blood of db / db mice, whereas MD001 treated db / db mice.
  • ALT and AST levels in blood were greatly reduced, and no change was seen in normal C57BL / 6 mice.
  • MD001 significantly decreased low density lipoprotein (LDL) levels and increased high density lipoprotein levels.
  • LDL low density lipoprotein
  • MD001 can be suggested to restore cholesterol metabolism in obese animals.
  • rosiglitazone induced a significant increase in liver weight (40%) and fat mass (50%) in db / db mice, whereas MD001 did not induce an increase in liver weight or adipose tissue mass.
  • MD001 was found to significantly reduce blood glucose and lipid content without weight loss and hepatotoxicity.
  • Fatty liver is a common complication of obesity, insulin resistance and type 2 diabetes, while PPAR ⁇ activity is known to stimulate fat consumption and reduced lipogenesis to improve fatty liver, whereas activated PPAR ⁇ has an opposite effect on fatty liver.
  • MD001 was identified as a PPAR ⁇ / ⁇ dual agonist, so that MD001 could relieve fatty liver in db / db mice.
  • rosiglitazone as known, exacerbated hepatic steatosis, whereas when MD001 was treated, the size and number of hepatic fat droplets decreased depending on the MD001 dose.
  • MD001 decreased liver TG and FFA, but did not reduce cholesterol, whereas rosiglitazone did not reduce liver TG.
  • MD001 significantly increased the expression of PPAR ⁇ target genes ACOX, CPT and MLYCD and the expression of PPAR ⁇ target genes GLUT2, GK, and CD36 as shown in FIG. 6E.
  • MD001 promotes ⁇ -oxidation to reduce hepatic steatosis or, in part, to reduce blood glucose levels by activating PPAR ⁇ .
  • MD001 was found to not only increase the absorption of fatty acids and glucose, but also partially promote ⁇ -oxidation in adipose tissue as shown in FIG. 7C.
  • Rosiglitazone was found to significantly increase the number of CLS in adipose tissue as shown in Figures 7D and 7E, while MD001 did not stimulate the inflammatory response of adipocytes.
  • H & E staining of skeletal muscle showed no difference between vehicle control, rosiglitazone and MD001 treatment groups in db / db mice.
  • MD001 significantly increased the expression of CPT, GLUT4, and lipoprotein lipase (LPL) in qRT-PCR analysis using skeletal muscle.
  • MD001 may be suggested to increase glucose and fatty acid metabolism in skeletal muscle.
  • MD001 may contribute to the improvement of hyperglycemia and hyperglycemia as a dual agonist of PPAR ⁇ / ⁇ .

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Abstract

La présente invention concerne une composition pour le traitement de maladies métaboliques contenant un nouveau composé ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif. En particulier, contrairement à la rosiglitazone, agoniste de PPARy, qui a été classiquement utilisé en tant qu'agent thérapeutique contre le diabète et présente des effets secondaires tels que l'hépatotoxicité, la détérioration du foie gras et la perte de poids, il a été confirmé que le composé de la présente invention exerce d'excellents effets dans le traitement du foie gras non alcoolique et de l'hyperlipidémie. En conséquence, une composition contenant en tant que principe actif le nouveau composé peut être utilisée en tant qu'agent thérapeutique pour le foie gras non alcoolique et l'hyperlipidémie et peut remplacer des agents thérapeutiques classiques.
PCT/KR2018/006649 2017-06-12 2018-06-12 NOUVEAU COMPOSÉ PRÉSENTANT UNE DOUBLE ACTIVITÉ PPARα/γ ET COMPOSITION POUR PRÉVENIR OU TRAITER UNE MALADIE MÉTABOLIQUE CONTENANT LEDIT COMPOSÉ EN TANT QUE PRINCIPE ACTIF WO2018230936A1 (fr)

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KR1020170073119A KR101934197B1 (ko) 2017-06-12 2017-06-12 PPARα/γ 이중 작용 활성을 갖는 신규 화합물 및 이를 유효성분으로 함유하는 대사질환 예방 또는 치료용 조성물

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894422A (zh) * 2022-12-26 2023-04-04 上海中医药大学 PPARγ激动剂及其组合和应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102269001B1 (ko) * 2019-09-09 2021-06-25 동국대학교 산학협력단 신규한 부타놀리드 이량체 화합물 및 이를 유효성분으로 함유하는 아디포넥틴 분비 촉진용 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4565882A (en) * 1984-01-06 1986-01-21 G. D. Searle & Co. Substituted dihydrobenzopyran-2-carboxylates
WO2002026729A2 (fr) * 2000-09-27 2002-04-04 Merck & Co., Inc. Derives d'acide benzopyrancarboxylique utilises pour le traitement du diabete et des troubles lipidiques
US20060089404A1 (en) * 2002-07-30 2006-04-27 Desai Ranjit C Ppar alpha selective compounds for the treatment of dyslipidemia and other lipid disorders
KR20150110901A (ko) * 2014-03-20 2015-10-05 현대약품 주식회사 Pparg에 결합하되 증진제로 작용하지 않는 화합물 및 이를 유효성분으로 함유하는 pparg 관련 질병의 치료용 약학적 조성물
KR20150118158A (ko) * 2013-02-22 2015-10-21 머크 샤프 앤드 돔 코포레이션 항당뇨병 비시클릭 화합물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4565882A (en) * 1984-01-06 1986-01-21 G. D. Searle & Co. Substituted dihydrobenzopyran-2-carboxylates
WO2002026729A2 (fr) * 2000-09-27 2002-04-04 Merck & Co., Inc. Derives d'acide benzopyrancarboxylique utilises pour le traitement du diabete et des troubles lipidiques
US20060089404A1 (en) * 2002-07-30 2006-04-27 Desai Ranjit C Ppar alpha selective compounds for the treatment of dyslipidemia and other lipid disorders
KR20150118158A (ko) * 2013-02-22 2015-10-21 머크 샤프 앤드 돔 코포레이션 항당뇨병 비시클릭 화합물
KR20150110901A (ko) * 2014-03-20 2015-10-05 현대약품 주식회사 Pparg에 결합하되 증진제로 작용하지 않는 화합물 및 이를 유효성분으로 함유하는 pparg 관련 질병의 치료용 약학적 조성물

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894422A (zh) * 2022-12-26 2023-04-04 上海中医药大学 PPARγ激动剂及其组合和应用

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