WO2024251233A1 - UTILISATION D'UN AGONISTE COMPLET DE PPAR EN COMBINAISON AVEC UN AGONISTE DE THR-β DANS LA RÉSISTANCE À DES MALADIES LIÉES AU MÉTABOLISME - Google Patents

UTILISATION D'UN AGONISTE COMPLET DE PPAR EN COMBINAISON AVEC UN AGONISTE DE THR-β DANS LA RÉSISTANCE À DES MALADIES LIÉES AU MÉTABOLISME Download PDF

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WO2024251233A1
WO2024251233A1 PCT/CN2024/097946 CN2024097946W WO2024251233A1 WO 2024251233 A1 WO2024251233 A1 WO 2024251233A1 CN 2024097946 W CN2024097946 W CN 2024097946W WO 2024251233 A1 WO2024251233 A1 WO 2024251233A1
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acid
agonist
thr
related diseases
mgl
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Chinese (zh)
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黄圣健
毛旭华
熊秋韵
张倩
潘德思
鲁先平
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Chengdu Chipscreen Pharmaceutical Ltd
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Chengdu Chipscreen Pharmaceutical Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the field of drug application, and in particular to the use of a PPAR full agonist combined with a THR- ⁇ agonist in preventing and/or improving and/or treating metabolic-related diseases.
  • Metabolic-related diseases are one of the important diseases that affect human health in the 21st century. It is estimated that 1/3 to 1/4 of the world's population will suffer from various metabolic-related diseases, such as obesity, diabetes, hyperlipidemia, chronic kidney disease, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) and corresponding complications. Among them, obesity, chronic kidney disease, and NASH currently have no safe and effective treatments, and there is a huge clinical need. Although these diseases can be alleviated to a certain extent through changes in lifestyle habits and interventions, patients with poor diet or exercise interventions still need drug treatment.
  • metabolic-related diseases such as obesity, diabetes, hyperlipidemia, chronic kidney disease, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) and corresponding complications.
  • NASH non-alcoholic fatty liver disease/non-alcoholic steatohepatitis
  • these diseases can be alleviated to a certain extent through changes in lifestyle habits and interventions,
  • PPAR ⁇ There are three subtypes of PPAR: PPAR ⁇ , PPAR ⁇ and PPAR ⁇ / ⁇ , each with its own unique biological function.
  • Sitagliptin developed by Shenzhen Chipscreen Biotech Co., Ltd. is a full PPAR agonist that fully stimulates all three subtypes.
  • Sitagliptin can effectively regulate blood sugar and improve insulin resistance in diabetic patients.
  • PPAR can also regulate the inflammatory response produced by various diseases.
  • THR thyroid hormone receptor
  • THR- ⁇ thyroid hormone receptor
  • the present invention provides a combination drug for preventing and/or improving and/or treating metabolic-related diseases.
  • the present invention provides the use of a PPAR full agonist combined with a THR- ⁇ agonist in the preparation of a drug for preventing and/or improving and/or treating metabolic-related diseases.
  • the PPAR full agonist is selected from cigliptin, fenofibrate, gemfibrozil, fenofibric acid, flufenamic acid, ibuprofen, bezafibrate, indomethacin, rosiglitazone, Ciprofibrate, valproic acid, dexibuprofen, amiodarone, prasterone, ⁇ -evening primrose oleic acid, PPM-204, clinofibrate, myrrh, palmitic acid, fenoprofen, lauric acid, stearic acid, clofibrate, docosahexaenoic acid, oleic acid, troglitazone, ⁇ -3 fatty acids, eicosapentaenoic acid, myristic acid, arachidonic acid, isoflavones, aleglitazar, repaglitazar, GFT505,
  • the PPAR full agonist is cigligliptin or any one or a combination of at least two of its pharmaceutically acceptable salts, isomers, solvates, and metabolites.
  • the pharmaceutically acceptable salt is any one of an alkali metal salt, an alkaline earth metal salt, an ammonium salt or a quaternary ammonium salt, preferably an alkali metal salt, and more preferably a sodium salt or a potassium salt.
  • the PPAR full agonist is sitagliptin sodium, sitagliptin potassium or their levorotatory isomer.
  • the THR- ⁇ agonist is selected from MGL-3196, ASC-41, HSK-31679, MB-07811, TERN-501, ABX-002, ALG-055009, ECC-4703, Kylo-0603, Sobetirome, VK-0214 or any one or a combination of at least two of the above-mentioned compounds in pharmaceutically acceptable salts, isomers, solvates, metabolites.
  • the THR- ⁇ agonist is MGL-3196 or any one of its pharmaceutically acceptable salts, isomers, solvates, metabolites, or a combination of at least two thereof.
  • the THR- ⁇ agonist is MGL-3196.
  • the unit dose of the PPAR full agonist is 1-50 mg, preferably 4-25 mg.
  • the unit dose of the THR- ⁇ agonist is 1-200 mg, preferably 5-150 mg.
  • the unit dose of sitagliptin sodium is 5-50 mg, preferably 10-20 mg, and more preferably 16 mg.
  • the unit dose of MGL-3196 is 50-150 mg, preferably 70-110 mg, more preferably 80 mg or 100 mg.
  • the metabolic-related diseases include obesity, hyperlipidemia, diabetes Disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and/or chronic kidney disease.
  • the metabolism-related diseases include obesity, hyperlipidemia, diabetes, non-alcoholic steatohepatitis (NASH) and/or chronic kidney disease.
  • the metabolism-related diseases are diabetes or non-alcoholic steatohepatitis (NASH).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a PPAR full agonist and a THR- ⁇ agonist as active ingredients, and one or more pharmaceutically acceptable excipients or carriers.
  • the PPAR full agonist is selected from cigliptin, fenofibrate, gemfibrozil, fenofibric acid, flufenamic acid, ibuprofen, bezafibrate, indomethacin, rosiglitazone, ciprofibrate, valproic acid, dexibuprofen, amiodarone, prasterone, ⁇ -evening primrose oleic acid, PPM-204, clibrate, myrrh, palmitic acid, fenoprofen, lauric acid, stearic acid, clofibrate, docosahexaenoic acid, oleic acid, troglitazone, ⁇ -3 fatty acids, eicosanoids, CPA, myristic acid, arachidonic acid, isoflavones, aleglitazar, repaglitazar, GFT50
  • the PPAR full agonist is cigligliptin or any one or a combination of at least two of its pharmaceutically acceptable salts, isomers, solvates, and metabolites.
  • the PPAR full agonist is sitagliptin sodium, sitagliptin potassium or their levorotatory isomer.
  • the THR- ⁇ agonist is selected from MGL-3196, ASC-41, HSK-31679, MB-07811, TERN-501, ABX-002, ALG-055009, ECC-4703, Kylo-0603, Sobetirome, VK-0214 or any one or a combination of at least two of the above-mentioned compounds in pharmaceutically acceptable salts, isomers, solvates, and metabolites.
  • the THR- ⁇ agonist is MGL-3196 or any one or a combination of at least two of its pharmaceutically acceptable salts, isomers, solvates, and metabolites.
  • the THR- ⁇ agonist is MGL-3196.
  • the unit dose of the PPAR full agonist is 1-50 mg, preferably 4-25 mg.
  • the unit dose of the THR- ⁇ agonist is 1-200 mg, preferably 5-150 mg.
  • the unit dose of sitagliptin sodium is 5-50 mg, preferably 10-20 mg, and more preferably 16 mg.
  • the unit dose of MGL-3196 is 50-150 mg, preferably 70-110 mg, more preferably 80 mg or 100 mg.
  • the dosage form of the pharmaceutical composition includes any one of tablets, powders, suspensions, granules, capsules, injections, sprays, solutions, enemas, emulsions, films, suppositories, patches, nasal drops or pills.
  • the present invention provides a medicine kit comprising the above-mentioned pharmaceutical composition.
  • the PPAR full agonist and THR- ⁇ agonist are unit preparations with the same or different specifications, respectively, and are placed in the same container or in different containers.
  • the present invention provides the above-mentioned pharmaceutical composition or the above-mentioned medicine kit for preventing and/or improving and/or treating metabolic-related diseases.
  • the present invention provides a method for preventing and/or improving and/or treating metabolic-related diseases, comprising administering a therapeutically effective amount of the above-mentioned pharmaceutical composition or the above-mentioned medicine kit to a patient in need.
  • the metabolic-related diseases include obesity, hyperlipidemia, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and/or chronic kidney disease. Still further, the metabolic-related diseases include obesity, hyperlipidemia, diabetes, non-alcoholic steatohepatitis (NASH) and/or chronic kidney disease. Still further, the metabolic-related diseases are diabetes or non-alcoholic steatohepatitis (NASH).
  • the combination of the PPAR full agonist Siglitstat sodium and the THR- ⁇ agonist MGL-3196 of the present invention can comprehensively and better reduce the body weight of diabetic mice, control blood sugar, regulate blood lipids, reduce liver and kidney damage and liver lipid accumulation, and reduce liver NAS score and fibrosis, and the combined effect is better than that of a single drug. It shows that the combination of PPAR full agonist and THR- ⁇ agonist has the effect of synergistically improving and treating metabolic-related diseases (such as obesity, hyperlipidemia, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and chronic kidney disease, etc.), and provides a better choice for the treatment of metabolic-related diseases.
  • metabolic-related diseases such as obesity, hyperlipidemia, diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and chronic kidney disease, etc.
  • Fig.2 Effects of different drug administration on animal liver-to-body weight ratio and liver lipid accumulation
  • the Contro1 group was the negative control group
  • the Vehicle group was the model group
  • the Chiglitazar group was the sitagliptin group
  • the MGL-3196 group was the MGL-3196 (Resmetirom) group
  • the Chiglitazar+MGL-3196 group was the sitagliptin and MGL-3196 combination group.
  • Type II diabetic BKS-db mice 8 weeks old, male; BKS-wt mice, 8 weeks old, male, weighing 21-24 g; all animals were purchased from Chengdu Yaokang Biotechnology Co., Ltd.
  • Chiglitazar used in this experiment was sourced from Chengdu Microchip Pharmaceutical Co., Ltd., and MGL-3196 (Resmetirom) was sourced from McLean (powder, content ⁇ 99%).
  • Sitagliptin sodium It has good water solubility and good stability within 1 week, so purified water is used as the solvent. A 1-w dosage can be prepared at a time and stored in a 4°C refrigerator for future use.
  • MGL-3196 dissolved in 0.2% CMC-Na + 0.1% Tween80, becomes a suspension after vortex ultrasound, and the dosage for 3 days is prepared at one time.
  • mice TC Elisa kit purchased from Nanjing Jiancheng Bioengineering Institute
  • mouse TG Elisa kit purchased from Nanjing Jiancheng Bioengineering Institute
  • Blood biochemistry analyzer model BS-240VET, brand Mindray
  • blood glucose meter model Performa Excellence Gold Collection, brand Roche
  • weighing scale centrifuge
  • dissection kit model Performa Excellence Gold Collection, brand Roche
  • microplate reader model Spark, brand Tecan
  • mice After the adaptive feeding, the mice were fasted but not watered for 6 hours. The fasting blood glucose and body weight of the mice were tested.
  • the BKS-db mice were randomly divided into 4 groups according to their fasting blood glucose and body weight, and the mice were given drugs, namely, Vehicle group, MGL-3196 group, Chiglitazar group, and Chiglitazar+MGL-3196 group.
  • the feed of the four groups of mice was changed.
  • the mice were fed with a Western diet containing 60% fat (purchased from Research Diet, USA) until the end of the experiment.
  • Chiglitazar 4mg/mL: Take 120mg of the test sample in a 50mL centrifuge tube, add 30mL of ultrapure water and mix well. Siglitazar sodium has good stability and can be prepared into a 1w dosage and placed in a 4°C refrigerator. Shake well before use.
  • MGL-3196 10mg/kg MGL-3196 (2mg/mL): Take 30mg of the test sample in a 50mL centrifuge tube, add 15mL of 0.2% CMC-Na + 0.1% Tween80 solution, vortex and ultrasonically mix, then administer the drug. The amount that can be prepared for 3 days should be stored in a 4°C refrigerator.
  • mice During the administration period, the basic conditions of the mice were observed every day, including the central and motor nervous systems, respiratory system, cardiovascular system, digestive system, urogenital system, skin, hair, eyes, etc.
  • mice The body weights of mice were measured once upon entering the room and upon grouping. During the drug administration period, all mice were weighed twice a week (Monday and Friday) until the end of the experiment.
  • mice The food intake of each group of mice was measured for 24 hours once a week, with fixed time points on Tuesday and Wednesday.
  • mice All mice were fasted for 6 hours but not water for blood glucose testing. The test was performed once when grouping and once every Thursday during the drug administration period.
  • mice All mice were fasted but not watered for 6 hours. After weighing, whole blood ( ⁇ 500uL) was collected from the eye sockets and placed in disposable procoagulant tubes. After standing for 5 minutes, the serum was separated by centrifugation (6000rpm, 5 minutes) and stored at -20°C for blood biochemical analysis.
  • the main indicators of blood biochemical analysis included four blood lipids, liver indicators, renal function and fasting blood sugar.
  • TC total cholesterol
  • TG triglycerides
  • HDL-C high-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • Renal function indicators blood urea nitrogen (BUN), serum creatinine (CREA).
  • the liver of each mouse was collected and weighed, and the liver weight ratio was calculated.
  • the middle lobe of the liver was removed and fixed with 10% neutral formalin for paraffin embedding (HE, SR staining) analysis.
  • NAS NASH activity score
  • liver fibrosis area percentage (Fibrosis Score) was scored based on the SR staining results, with a score of 0-4, representing different degrees of fibrosis severity.
  • the left lobe of the liver was taken and divided into two parts, which were quickly frozen in liquid nitrogen and stored in a -80°C refrigerator for the determination of liver lipid content.
  • the total cholesterol and triglyceride content in the mouse liver were detected using mouse TG and TC Elisa kits.
  • sitagliptin and MGL-3196 can reduce the body weight of diabetic mice fed a high-fat diet, and is superior to the single-drug group. This shows that when sitagliptin and MGL-3196 are used in combination to treat obesity, the combination of the two drugs achieves a synergistic effect and has better effects than the two single drugs.
  • the Vehicle group had significantly increased fasting blood glucose and possessed the model characteristics of diabetic mice.
  • the sitagliptin monotherapy group had a significant effect on lowering blood glucose in animals, which was consistent with the characteristics of the drug;
  • the MGL-3196 monotherapy group had a trend of improving blood glucose, but there was no significant difference compared with the Vehicle group.
  • the combination group was able to significantly reduce the blood glucose level of diabetic mice compared with the Vehicle group or the MGL-3196 monotherapy group, and there was also a trend of improving blood glucose compared with the sitagliptin monotherapy group (Figure 1.B).
  • sitagliptin and MGL-3196 can reduce the blood glucose of high-fat-fed diabetic mice, and is superior to the single-drug group. This shows that when sitagliptin and MGL-3196 are used in combination to treat diabetes, the combination of the two drugs achieves a synergistic effect and has better effects than the two single drugs.
  • the liver of diabetic mice fed a high-fat diet was significantly enlarged, and the liver/body weight ratio was significantly increased compared with the Control group.
  • the MGL-3196 monotherapy group was able to significantly reduce the liver-body weight ratio of the animals, and the sitagliptin monotherapy group also had a trend of reducing the liver-body weight ratio.
  • the combined administration group was able to further reduce the liver-body weight ratio of the animals on the basis of the monotherapy, and it was close to the value of normal animals, indicating that it has a good improvement effect on liver function (Figure 2.A).
  • the animals in the Vehicle group had more obvious accumulation of TG and TC in the liver.
  • the sitagliptin monotherapy group and the MGL-3196 monotherapy group can significantly reduce the TG content in the mouse liver, and the combined drug group can further reduce its content, which is significantly different from the Vehicle group ( Figure 2.B).
  • the sitagliptin monotherapy group and the MGL-3196 monotherapy group can also tend to reduce the TC content in the mouse liver, and the combined drug group can significantly reduce its content compared with the Vehicle group, and there is also a trend of improving liver lipid accumulation compared with the single drug (Figure 2.C).
  • sitagliptin and MGL-3196 has a significant improvement effect on the liver weight ratio and liver lipid accumulation of diabetic mice fed with high fat, and is better than the single drug group. This shows that when sitagliptin and MGL-3196 are used in combination to treat NASH, the combined use of the two drugs achieves a synergistic effect and has a better effect than the two single drugs.
  • Serum biochemistry tests were then performed, including four blood lipid tests, two liver function tests, and two kidney function tests.
  • the four blood lipid tests of this model showed: slightly elevated TG, significantly elevated TC and LDL-C, and significantly reduced HDL-C, indicating that diabetic mice fed a high-fat diet had the characteristics of hyperlipidemia.
  • the sitagliptin monotherapy group or the MGL-3196 monotherapy group had no significant effect on serum TG, but After combined use, serum TG levels can still be significantly reduced compared with Vehicle, and a trend of combined use is shown compared with the two single drugs (Figure 3.A).
  • sitagliptin and MGL-3196 can reduce TG and increase HDL-C in diabetic mice fed with high fat, and is better than the single drug group. This indicates that when sitagliptin and MGL-3196 are used in combination to treat hyperlipidemia, the two drugs achieve a synergistic effect and have better effects than either drug alone.
  • ALT and AST were significantly increased in the model animals (Vehicle group) (compared with the Control group), indicating that the animals had inflammatory liver damage.
  • both sitagliptin and MGL-3196 alone can reduce the levels of the two liver enzymes in the animal serum, indicating an improvement in liver function, and the combination of drugs can further reduce the two liver enzymes on the basis of single drugs, indicating that the combination of drugs has the potential to improve liver damage ( Figure 3.E-F).
  • the combination of sitagliptin and MGL-3196 can reduce ALT and AST in high-fat-fed diabetic mice, and is superior to the single-drug group. It shows that when sitagliptin and MGL-3196 are used in combination to treat NASH, the combined use of the two drugs achieves a synergistic effect and has better effects than the two single drugs.
  • This model also has a certain degree of renal damage.
  • the serum creatinine of the animals in the Vehicle group increased significantly (Figure 3.G) and urea nitrogen also had a certain upward trend (Figure 3.H).
  • both single drugs can reduce serum creatinine well, among which the reduction level of sitagliptin sodium alone is better than that of MGL-3196 alone, and the combined administration further reduced the serum creatinine level on the basis of single drugs ( Figure 3.G).
  • the two single drugs had a tendency to reduce its level, but the combined drug treatment could significantly reduce serum urea nitrogen compared with the Vehicle group, and the combined administration further reduced the serum urea nitrogen level on the basis of single drugs (Figure 3.H).
  • sitagliptin sodium and MGL-3196 can reduce serum creatinine and urea nitrogen in high-fat-fed diabetic mice, and is better than the single drug group. It shows that when sitagliptin sodium and MGL-3196 are used in combination to treat chronic kidney disease, the combined use of the two drugs achieves a synergistic effect and has better effects than the two single drugs.
  • NAS score is a comprehensive evaluation method for NASH disease pathology, including liver steatosis, Inflammation and ballooning, with a total score of 8 points.
  • the NAS assessment of the model group was about 6 points, which was a NASH model with moderate inflammation.
  • sitagliptin monotherapy or MGL-3196 monotherapy could reduce the NAS score to about 4 points, with good monotherapy effects, and the combination of drugs could further reduce the NAS score on the basis of monotherapy, indicating that the combination of drugs can better improve the pathological condition of NASH patients (Figure 4.A).
  • this model is a mild liver fibrosis model, with an average liver fibrosis score of less than 1 point.
  • sitagliptin and MGL-3196 still have a trend to improve liver fibrosis, and the combination of drugs can significantly reduce its fibrosis score compared with the Vehicle group, indicating that the combination of drugs has the potential to improve liver fibrosis in NASH patients (Figure 4.B).
  • the combination of sitagliptin and MGL-3196 can reduce the NAS score and liver fibrosis score of high-fat-fed diabetic mice, and is better than the single-drug group. This indicates that when sitagliptin and MGL-3196 are used in combination to treat NASH, the two drugs achieve a synergistic effect and have better effects than either drug alone.
  • the diabetic mice fed a high-fat diet of the present invention simulate metabolic syndromes such as diabetes, obesity, hyperlipidemia, NASH and chronic kidney disease.
  • Sitagliptin sodium or MGL-3196 alone can reduce the body weight, an indicator of obesity, reduce the TG, an indicator of hyperlipidemia, increase the HDL-C, an indicator of hyperlipidemia, and reduce the serum creatinine and urea nitrogen, indicators of chronic kidney disease.
  • the combination of drugs can further improve these indicators, achieving a synergistic effect.
  • Siglistat combined with MGL-3196 can significantly lower the blood sugar of diabetic mice, and the effect is better than that of sitagliptin alone and MGL-3196 alone, achieving a synergistic effect, indicating that the combination of the two can be used to treat metabolic-related diseases such as diabetes.
  • sitagliptin and MGL-3196 significantly reduced the increased liver-to-body weight ratio, liver lipid accumulation, increased liver function ALT and AST, NAS and high liver fibrosis scores in mice with NASH disease characteristics.
  • the reduction effect was better than that of sitagliptin and MGL-3196 alone, achieving a synergistic effect, indicating that the combination of the two can be used to treat metabolic-related diseases such as NASH.
  • sitagliptin and MGL-3196 has the potential and clinical value to greatly improve or treat metabolic-related diseases such as diabetes, obesity, hyperlipidemia, NASH and chronic kidney disease.

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Abstract

L'invention concerne l'utilisation d'un agoniste complet de PPAR en combinaison avec un agoniste de THR-β dans la préparation d'un médicament destiné à prévenir et/ou à atténuer et/ou à traiter des maladies liées au métabolisme. L'agoniste complet de PPAR en combinaison avec l'agoniste de THR-β peut réduire globalement et de façon améliorée la masse corporelle de souris diabétiques, réguler la glycémie, réguler les lipides sanguins, réduire des lésions hépatiques et rénales et l'accumulation de lipides dans le foie et réduire le score NAS et la fibrose hépatiques, indiquant que l'agoniste complet de PPAR en combinaison avec l'agoniste de THR-β présente le potentiel d'atténuer et de traiter des maladies liées au métabolisme.
PCT/CN2024/097946 2023-06-08 2024-06-07 UTILISATION D'UN AGONISTE COMPLET DE PPAR EN COMBINAISON AVEC UN AGONISTE DE THR-β DANS LA RÉSISTANCE À DES MALADIES LIÉES AU MÉTABOLISME Ceased WO2024251233A1 (fr)

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