WO2022135461A1 - Use of magl inhibitor in preparation of medicament for preventing or treating fatty liver diseases - Google Patents
Use of magl inhibitor in preparation of medicament for preventing or treating fatty liver diseases Download PDFInfo
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- WO2022135461A1 WO2022135461A1 PCT/CN2021/140422 CN2021140422W WO2022135461A1 WO 2022135461 A1 WO2022135461 A1 WO 2022135461A1 CN 2021140422 W CN2021140422 W CN 2021140422W WO 2022135461 A1 WO2022135461 A1 WO 2022135461A1
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- WIPO (PCT)
- Prior art keywords
- maglz
- fatty liver
- alcoholic
- liver
- liver disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- 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
Definitions
- the invention belongs to the field of medicine, and relates to the use of a MAGL inhibitor in the preparation of a medicine for preventing or treating fatty liver disease.
- FLD Fatty Liver Disease
- FLD is a clinicopathological syndrome characterized by excessive accumulation of fat in liver cells and steatosis. Obesity, alcohol consumption, diabetes, malnutrition, some drugs, pregnancy and infection are risk factors for FLD. According to histological features, FLD is divided into fatty liver and steatohepatitis; according to the presence or absence of long-term excessive drinking, it is divided into non-alcoholic fatty liver disease and alcoholic fatty liver disease.
- Non-Alcoholic Fatty Liver Disease NASH
- NASH Non-Alcoholic Fatty Liver Disease
- the prevalence of non-alcoholic fatty liver disease in the global general population is as high as 20%, and there is a trend of younger age. It is estimated that in the future, more than one-third of people worldwide will be at risk of developing non-alcoholic fatty liver disease, significantly exceeding the incidence of hepatitis B, hepatitis C and alcoholic liver disease, and has become the most common clinical liver disease. .
- Non-alcoholic fatty liver disease can be divided into non-alcoholic simple fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and related liver cirrhosis and liver cancer according to its pathology.
- NAFL non-alcoholic simple fatty liver
- NASH non-alcoholic steatohepatitis
- liver cirrhosis and liver cancer according to its pathology.
- NAFLD generally includes three types of simple fatty liver and its evolved steatohepatitis (NASH) and liver cirrhosis.
- NASH evolved steatohepatitis
- hepatitis C, autoimmune liver disease, Wilson disease, etc. can also cause hepatic steatosis, because the main body of the disease is in the portal area and has a specific name, it does not belong to the category of common fatty liver disease.
- the pathogenesis of fatty liver is still not fully understood. At present, it is believed that the "second hit" theory may be the common pathogenesis of alcoholic fatty liver and non-alcoholic fatty liver.
- Alcohol, obesity, diabetes, etc. as the first attack, cause fat storage to form simple fatty liver by causing the imbalance between triglyceride synthesis and metabolism in liver cells; the second attack refers to the lipid peroxidation related to oxygen stress and
- the action of inflammatory cytokines leads to inflammation, necrosis and fibrosis of steatotic hepatocytes.
- the difference is that the occurrence of fatty liver in alcoholic is mainly caused by ethanol and its metabolites, while in non-alcoholic it is mainly related to insulin resistance.
- Disorders of lipid metabolism are common in NAFLD patients.
- the liver plays a major role in lipid metabolism in the body. It can take in free fatty acids, process, store and export lipids.
- Free fatty acids play important roles in cells, such as synthesizing cell membranes, serving as energy storage, and participating in intracellular signaling pathways.
- chronic increases in free fatty acids in many organs disrupt metabolic pathways and induce insulin resistance.
- the accumulation of lipids in the liver is closely related to restriction. Adipose tissue insulin resistance increases lipolysis and increases the input of free fatty acids from adipose tissue to the liver, reducing output.
- non-alcoholic fatty liver disease If non-alcoholic fatty liver disease is not treated in time, it will turn into non-alcoholic liver cirrhosis complicated by liver cancer, which will seriously affect people's life and health. Weight loss is the basic measure to prevent the occurrence of NAFLD in obese people. Cytoprotective agents, antioxidants and lipid-lowering drugs have certain therapeutic effects on NAFLD. The clinical treatment of thiazolidinediones (such as rosiglitazone) has achieved promising results. . Several drugs have been used in clinical trials for NAFLD and NASH, but they have not been recommended due to inconsistent outcomes and/or lack of therapeutic benefit in randomized controlled trials. Therefore, it is particularly important to develop effective drugs to intervene to prevent NAFLD disease progression.
- Alcoholic Hepatitis is a liver disease caused by long-term heavy drinking.
- the initial stage is usually fatty liver, which can progress to alcoholic hepatitis, liver fibrosis and cirrhosis.
- ALD ALD-deficiency
- Drug treatment mainly includes the application of lipid-lowering drugs and hepatoprotective drugs, but these drugs have some serious deficiencies.
- many blood lipid-lowering drugs can promote the metabolism of blood lipids more concentrated in the liver, but may promote the accumulation of lipids in the liver and further damage the liver function; and these drugs need to be taken for a long time and are expensive. Therefore, it is very necessary to actively search for drugs with liver protection, blood lipid lowering and anti-fatty liver functions.
- the purpose of the present invention is to provide the use of the compound MAGLZ-II-11 of the present invention in the preparation of a medicament for preventing or treating fatty liver disease.
- MAGLZ-II-11 of the present invention can significantly reduce the body weight and liver index of non-alcoholic fatty liver disease, reduce serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduce liver homogenate free fatty acid (FFA), glycerol.
- Triester (TG) level has a significant effect on the treatment of non-alcoholic fatty liver disease, and its therapeutic effect is good and the safety is high.
- the MAGLZ-II-11 of the present invention has a significant therapeutic effect on alcoholic fatty liver, can reduce serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) content, Has significant lipid-lowering and hepatoprotective effects.
- ALT serum alanine aminotransferase
- AST aspartate aminotransferase
- TG triglyceride
- MAGLZ-II-11 of the present invention has the following structural formula:
- the present application provides the use of the compound MAGLZ-II-11 of the present invention for preventing or treating fatty liver disease, wherein the fatty liver disease is non-alcoholic fatty liver disease or alcoholic liver disease.
- the non-alcoholic fatty liver disease is non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver fibrosis or non-alcoholic fatty liver cirrhosis.
- the alcoholic liver disease is alcoholic hepatitis, alcoholic fatty liver disease, alcoholic liver fibrosis, or alcoholic liver cirrhosis.
- Example 1 The effect of MAGLZ-II-11 on non-alcoholic fatty liver disease in rats caused by high-fat diet was studied. The results showed that MAGLZ-II-11 significantly reduced body weight, liver index, serum alanine aminotransferase and aspartate aminotransferase. The level of free fatty acid and triglyceride in liver homogenate can be reduced, and the liver function damage can be improved.
- the MAGLZ-II-11 of the present invention has a significant effect on treating non-alcoholic fatty liver disease.
- Example 2 The effect of MAGLZ-II-11 on non-alcoholic fatty liver disease in high-fat diet/fructose model mice was studied. The results showed that MAGLZ-II-11 reduced serum alanine aminotransferase and aspartate aminotransferase. Enzyme and triglyceride levels.
- Example 3 shows that MAGLZ-II-11 significantly reduces the levels of alanine aminotransferase and aspartate aminotransferase, and has a protective effect on the liver function of alcoholic fatty liver in rats.
- MAGLZ-II-11 significantly decreased serum triglyceride, total cholesterol and low-density lipoprotein cholesterol content in alcoholic fatty liver rats, and increased serum high-density lipoprotein cholesterol content, indicating that MAGLZ-II-11 has the effect of regulating blood lipids.
- the present application provides the use of MAGLZ-II-11 of the present invention in the manufacture of a product for treating and/or preventing fatty liver disease from gaining body weight and/or liver weight.
- the present application provides the increase of aspartate aminotransferase and/or alanine aminotransferase in the serum of MAGLZ-II-11 of the present invention in the preparation of treatment and/or prevention of fatty liver disease patients application in the product.
- the present application provides the use of MAGLZ-II-11 of the present invention in the manufacture of a product for treating and/or preventing increased triglycerides and/or free fatty acids in fatty liver disease-affected subjects.
- the product is a nutraceutical or a drug.
- the product for treating and/or preventing fatty liver disease is a medicine, and the medicine includes MAGLZ-II-11 and pharmaceutically acceptable excipients.
- the medicament for treating and/or preventing fatty liver disease includes various acceptable dosage forms.
- the dosage form of MAGLZ-II-11 of the present invention is not particularly limited, for example, it may be an oral dosage form or an injection dosage form.
- the oral dosage form can be a liquid dosage form or a solid dosage form.
- the oral dosage form is selected from hard capsules, soft capsules, slow-release capsules, compressed tablets, sugar-coated tablets, powders, granules, dropping pills, honeydew pills, syrup or oral liquid;
- the injection dosage form is selected from solution type, suspension Liquid, emulsion or lyophilized powder.
- the administration mode of MAGLZ-II-11 for preventing and/or treating fatty liver disease can be oral, drip or injection.
- the tablet When preparing a solid preparation for oral use, after adding an excipient and optionally a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. to the main drug, the tablet can be prepared according to a conventional method. , coated tablets, granules, fine granules, powders, capsules, etc.
- the excipient can be selected from one or more of lactose, corn starch, glucose, sorbitol, crystalline cellulose and silicon dioxide.
- binder it can be selected from one or more of polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.
- magnesium stearate As the lubricant, one or more of magnesium stearate, talc and silicon dioxide can be selected.
- cocoa powder As a flavoring agent, one or more of cocoa powder, menthol, aromatic acid, peppermint oil, borneol and cinnamon powder can be used.
- the above-mentioned tablets and granules can also be coated with sugar coating, gelatin coating, and other necessary outer coatings.
- pH adjusters, buffers, suspending aids, solubilizers, stabilizers, isotonic agents, preservatives, etc. can be added to the main drug as required, and then intravenous, subcutaneous, and intramuscular injections can be prepared according to conventional methods. . At this time, if necessary, a freeze-dried product can be prepared by a conventional method.
- suspending aid it can be selected from one or more of methyl cellulose, Tween 80, hydroxyethyl cellulose, gum arabic, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate .
- solubilizer it can be selected from one or more of polyoxyethylene hydrogenated castor oil, Tween 80, nicotinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol, and castor oil fatty acid ethyl ester.
- a stabilizer it can be selected from one or more of sodium sulfite and sodium metabisulfite; as a preservative, it can be selected from methylparaben, ethylparaben, sorbic acid, phenol, cresol, One or more of chlorocresol.
- the MAGLZ-II-11 of the present invention is administered to a subject, which may be a mammal, such as a human, a rat, a rabbit, a sheep, a pig, a cow, a cat, a dog, a monkey, etc., preferably a human.
- a subject which may be a mammal, such as a human, a rat, a rabbit, a sheep, a pig, a cow, a cat, a dog, a monkey, etc., preferably a human.
- the preparation methods of the above-mentioned pharmaceutical preparations can be prepared by those skilled in the art by conventional preparation methods for preparing such dosage forms.
- the content of the compound of the present invention contained in each preparation unit is 0.001 mg to 50 mg.
- the MAGLZ-II-11 of the present invention has a significant therapeutic effect on non-alcoholic fatty liver disease, and can significantly reduce body weight, liver index, serum ALT and AST levels, and liver homogenate FFA and TG levels, and improve liver function damage.
- MAGLZ-II-11 has a significant effect on the treatment of non-alcoholic fatty liver disease.
- MAGLZ-II-11 has good development and application value in the prevention or treatment of non-alcoholic fatty liver disease.
- the MAGLZ-II-11 of the present invention has a significant therapeutic effect on alcoholic fatty liver, can reduce ALT, AST, reduce TG content, TC content and LDL-C content, increase serum HDL-C content, and has significant lipid-lowering and liver-protecting effects effect.
- Fig. 1 The liver pathological sections of each group in Example 2.
- compounds MAGLZ-II-2, MAGLZ-II-10, MAGLZ-II-11, and MAGLZ-II-17 were prepared according to the methods in the invention patent with the application number of 201910836454.5.
- SD rats weighing 140-180g, male, 72, were randomly divided into 9 groups, namely blank group, model group, JZL184 group, MAGLZ-II-2 group, MAGLZ-II-10 group, MAGLZ-II-17 group , MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
- Serum ALT, AST, liver homogenate TG, FFA content were detected.
- the abdominal cavity of the rats in the model group was hypertrophic, with abundant adipose tissue, significantly increased liver volume, tight capsule, brick red, greasy cut surface, and typical appearance of fatty liver; The content is small, the liver volume is slightly larger and yellowish, and part of the liver section has a greasy feeling.
- Table 1 shows that the body weight and liver index of each MAGLZ-II-11 group were significantly lower than those of the model group. Compared with the model group, the body weight and liver index of each MAGLZ-II-11 group were significantly different.
- Table 2 shows that the activities of ALT and AST increased in different degrees in each model group.
- the FFA and TG of liver homogenate were the highest in the model group and the lowest in the blank group.
- 8-week-old C57BL/6N mice 64 mice, were divided into 8 groups after one week of adaptation to the new environment, normal group, model group, MAGLZ-II-2 group, MAGLZ-II-10 group, MAGLZ-II-17 group , MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
- mice in the normal group were fed with normal chow, and the mice in the model group and the mice in the administration group were fed with high-fat diet (HFD) for eight weeks.
- HFD high-fat diet
- the normal control group was given normal drinking water and normal diet, and the mice in the model group and the mice in the administration group were given high-fructose and high-glucose drinking water (23.1g fructose and 18.9g glucose were added to 1L of water) and continued to be given high-fructose and high-glucose drinking water. After 8 weeks of fat diet.
- mice in the administration group were administered once a day for 14 consecutive days.
- each group was given 0.5% sodium carboxymethyl cellulose and corresponding drugs respectively.
- the administration of each group was as follows:
- MAGLZ-II-2 group 16mg/kg MAGLZ-II-2;
- MAGLZ-II-10 group 16mg/kg MAGLZ-II-10;
- MAGLZ-II-17 group 16mg/kg MAGLZ-II-17;
- MAGLZ-II-11 low-dose group 4 mg/kg MAGLZ-II-11;
- MAGLZ-II-11 medium dose group 8 mg/kg MAGLZ-II-11;
- MAGLZ-II-11 high-dose group 16 mg/kg MAGLZ-II-11.
- mice were sacrificed after 14 days, and mouse body weight and liver tissue were weighed.
- liver histological characteristics were analyzed by hematoxylin and eosin (HE) staining.
- Other tissues were collected and frozen in liquid nitrogen for use, and serum was collected to measure metabolite parameters.
- liver pathological sections showed that the liver of the model group contained a large number of fat granules with severe inflammation and necrosis, while the MAGLZ-II-11 groups had fewer fat granules and milder inflammation, as shown in Figure 1.
- SD rats, 72, weighing 180-220g, half male and half male were randomly divided into 9 groups, namely control group, model group, JZL184 group, MAGLZ-II-2 group, MAGLZ-II-10 group, MAGLZ-II- 17 groups, MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
- the control group was given normal saline by gavage and fed with normal feed; the rest of the rats were given free access to 10% alcohol and fed high-nutrient feed (normal feed supplemented with 10% whole milk powder, 10% egg yolk powder, 10% refined lard, etc.) after 6 weeks , divided into model group and each administration group, continued to feed high-nutrition feed and drink 10% alcohol for 4 weeks, and at the same time began to give drugs or distilled water by gavage for 4 weeks. 24 hours after the last administration, the orbits were bled, the serum was separated, and the serum liver function was measured; the animals were sacrificed, the liver homogenate was prepared, and the blood lipids of liver cells and the indexes of liver lipid peroxidation were measured.
- the MAGLZ-II-11 group can significantly reduce the elevated ALT and AST, indicating that MAGLZ-II-11 has a protective effect on the liver function of alcoholic fatty liver in rats.
- MAGLZ-II-11 high-dose group can significantly reduce the serum TG, TC and LDL-C contents in alcoholic fatty liver rats, and increase the serum HDL-C contents, with significant difference.
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Abstract
Use of MAGLZ-II-11 in the preparation of a medicament for preventing or treating fatty liver diseases. MAGLZ-Ⅱ-11 can significantly reduce the body weight and liver indexes in non-alcoholic fatty liver disease patients, reduce the levels of serum glutamic pyruvic transaminase and glutamic oxalacetic transaminase, and reduce the levels of free fatty acids and triglycerides in liver homogenates, having significant effects in the treatment of non-alcoholic fatty liver diseases and having good therapeutic effects and high safety. MAGLZ-II-11 has significant therapeutic effects on alcoholic fatty liver, and has significant lipid-lowering and liver-protecting effects.
Description
本发明属于医药领域，涉及MAGL抑制剂在制备预防或治疗脂肪性肝病药物中的用途。The invention belongs to the field of medicine, and relates to the use of a MAGL inhibitor in the preparation of a medicine for preventing or treating fatty liver disease.
脂肪性肝病(Fatty Liver Disease，FLD)是以肝细胞脂肪过度贮积和脂肪变性为特征的临床病理综合征。肥胖、饮酒、糖尿病、营养不良、部分药物、妊娠以及感染等是FLD发生的危险因素。根据组织学特征，将FLD分为脂肪肝和脂肪性肝炎；根据有无长期过量饮酒的病因，有分为非酒精性脂肪性肝病和酒精性脂肪性肝病。Fatty Liver Disease (FLD) is a clinicopathological syndrome characterized by excessive accumulation of fat in liver cells and steatosis. Obesity, alcohol consumption, diabetes, malnutrition, some drugs, pregnancy and infection are risk factors for FLD. According to histological features, FLD is divided into fatty liver and steatohepatitis; according to the presence or absence of long-term excessive drinking, it is divided into non-alcoholic fatty liver disease and alcoholic fatty liver disease.
随着人民生活方式和饮食结构的改变，长期高脂饮食极易导致非酒精性脂肪肝病(Non-Alcoholic Fatty Liver Disease，NAFLD)的发生。目前，全球普通人群中非酒精性脂肪肝病患病率高达20％以上，且有低龄化趋势。据估计未来全世界范围内将会有三分之一以上的人患非酒精性脂肪肝病的危险，明显超过乙型肝炎、丙型肝炎及酒精性肝病的发病率，已成为临床最常见的肝病。With the change of people's lifestyle and dietary structure, long-term high-fat diet can easily lead to the occurrence of Non-Alcoholic Fatty Liver Disease (NAFLD). At present, the prevalence of non-alcoholic fatty liver disease in the global general population is as high as 20%, and there is a trend of younger age. It is estimated that in the future, more than one-third of people worldwide will be at risk of developing non-alcoholic fatty liver disease, significantly exceeding the incidence of hepatitis B, hepatitis C and alcoholic liver disease, and has become the most common clinical liver disease. .
非酒精性脂肪肝病按其病理可分为非酒精单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及相关的肝硬化和肝癌。Non-alcoholic fatty liver disease can be divided into non-alcoholic simple fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and related liver cirrhosis and liver cancer according to its pathology.
NAFLD在病理上一般包括单纯性脂肪肝以及由其演变的脂肪性肝炎(NASH)和肝硬化三种类型。尽管丙型肝炎、自身免疫性肝病、Wilson病等亦可导致肝脂肪变，但因其病变主体在汇管区，且有特定命名，故不属于普通脂肪性肝病的范畴。脂肪肝的发病机制至今尚未完全清楚。目前认为，“二次打击”学说可能是酒精性脂肪肝和非酒精性脂肪肝共同的发病机制。酒精、肥胖、糖尿病等作为初次打击，通过引起肝细胞内甘油三酯合成和代谢之间失衡导致脂肪贮积形成单纯性脂肪肝；第二次打击是指氧应激相关的脂质过氧化及炎性细胞因子的作用，导致脂肪变的肝细胞发生炎症、坏死和纤维化。不同的是脂肪肝的发生在酒精性主要由乙醇及其代谢产物所致，而在非酒精性则主要与胰岛素抵抗有关。在NAFLD 患者中，脂质代谢紊乱比较常见。肝脏在体内脂质代谢过程中发挥着主要的作用，它能够摄入游离脂肪酸，加工、贮存和输出脂质，过程中的任何一环出现问题都可能导致NAFLD的产生。游离脂肪酸在细胞中发挥着重要作用，例如合成细胞膜、作为能量存储以及参与细胞内的信号通路。然而，在很多器官中慢性的游离脂肪酸含量的增加会破坏代谢途径，诱导胰岛素抵抗。肝脏中脂质的积累与限密切相关。脂肪组织胰岛素抵抗能增加脂解并且能增加游离脂肪酸从脂肪组织到肝脏的输入，减少输出。Pathologically, NAFLD generally includes three types of simple fatty liver and its evolved steatohepatitis (NASH) and liver cirrhosis. Although hepatitis C, autoimmune liver disease, Wilson disease, etc. can also cause hepatic steatosis, because the main body of the disease is in the portal area and has a specific name, it does not belong to the category of common fatty liver disease. The pathogenesis of fatty liver is still not fully understood. At present, it is believed that the "second hit" theory may be the common pathogenesis of alcoholic fatty liver and non-alcoholic fatty liver. Alcohol, obesity, diabetes, etc., as the first attack, cause fat storage to form simple fatty liver by causing the imbalance between triglyceride synthesis and metabolism in liver cells; the second attack refers to the lipid peroxidation related to oxygen stress and The action of inflammatory cytokines leads to inflammation, necrosis and fibrosis of steatotic hepatocytes. The difference is that the occurrence of fatty liver in alcoholic is mainly caused by ethanol and its metabolites, while in non-alcoholic it is mainly related to insulin resistance. Disorders of lipid metabolism are common in NAFLD patients. The liver plays a major role in lipid metabolism in the body. It can take in free fatty acids, process, store and export lipids. Problems in any part of the process may lead to the production of NAFLD. Free fatty acids play important roles in cells, such as synthesizing cell membranes, serving as energy storage, and participating in intracellular signaling pathways. However, chronic increases in free fatty acids in many organs disrupt metabolic pathways and induce insulin resistance. The accumulation of lipids in the liver is closely related to restriction. Adipose tissue insulin resistance increases lipolysis and increases the input of free fatty acids from adipose tissue to the liver, reducing output.
非酒精性脂肪肝病如不及时治疗，将会转变非酒精性肝硬化并发肝癌，严重影响着人民的生活与健康。减轻体重是预防肥胖者发生NAFLD的基本措施，细胞保护剂、抗氧化剂和降脂药物对NAFLD有一定治疗作用，噻唑脘二酮类(如罗格列酮)的临床治疗研究已取得可喜的疗效。目前已有几种药物被应用于NAFLD和NASH的临床试验中，但是由于出现了与预期不一致的结局和(或)在随机对照试验中缺乏治疗效益，尚未被推荐使用。因此，开发有效的药物进行干预，阻止NAFLD疾病进展就显得尤为重要。If non-alcoholic fatty liver disease is not treated in time, it will turn into non-alcoholic liver cirrhosis complicated by liver cancer, which will seriously affect people's life and health. Weight loss is the basic measure to prevent the occurrence of NAFLD in obese people. Cytoprotective agents, antioxidants and lipid-lowering drugs have certain therapeutic effects on NAFLD. The clinical treatment of thiazolidinediones (such as rosiglitazone) has achieved promising results. . Several drugs have been used in clinical trials for NAFLD and NASH, but they have not been recommended due to inconsistent outcomes and/or lack of therapeutic benefit in randomized controlled trials. Therefore, it is particularly important to develop effective drugs to intervene to prevent NAFLD disease progression.
酒精性肝病(Alcoholic Hepatitis，ALD)是由于长期大量饮酒导致的肝脏疾病。初期通常表现为脂肪肝，进而可发展成酒精性肝炎、肝纤维化和肝硬化。Alcoholic Hepatitis (ALD) is a liver disease caused by long-term heavy drinking. The initial stage is usually fatty liver, which can progress to alcoholic hepatitis, liver fibrosis and cirrhosis.
ALD的临床表现与肝脏脂肪浸润的程度成正比，在肝内过多的脂肪被移除后症状可消失。临床上以肝肿大为最常见体征，其次为肝区痛及压痛。少数病人可有轻度黄疸，实验室检查提示与胆道系统阻塞有关。重症患者可以有腹水和下肢水肿，偶见脾肿大。部分患者可以伴有维生素缺乏表现，如周围神经炎、舌炎、口角炎、皮肤瘀斑等。The clinical manifestations of ALD are proportional to the degree of fatty infiltration of the liver, which disappears after the excess fat in the liver is removed. Clinically, hepatomegaly is the most common sign, followed by liver pain and tenderness. A small number of patients may have mild jaundice, and laboratory tests suggest that it is related to obstruction of the biliary system. Severely ill patients may have ascites and lower extremity edema, and occasionally splenomegaly. Some patients may be accompanied by symptoms of vitamin deficiency, such as peripheral neuritis, glossitis, angular stomatitis, and skin ecchymosis.
目前临床上对于ALD的治疗仍缺乏特效手段，主要采用病因治疗、支持疗法，予以饮食控制，补充氨基酸、维生素和矿物质等对症治疗。药物治疗主要包括降脂类药物和保肝类药物的应用，但这些药物均存在一些严重的不足之处。如许多降血脂药可促进血脂更集中于肝脏进行代谢，反而可能促进脂质在肝内的蓄积，并进一步损害肝功能；且这些药物需长期服用，价格昂贵。因此，积极寻找具有保肝、降血脂、抗脂肪肝的药物是非常必要的。At present, the clinical treatment of ALD still lacks effective means, mainly using etiological treatment, supportive therapy, dietary control, supplementation of amino acids, vitamins and minerals and other symptomatic treatments. Drug treatment mainly includes the application of lipid-lowering drugs and hepatoprotective drugs, but these drugs have some serious deficiencies. For example, many blood lipid-lowering drugs can promote the metabolism of blood lipids more concentrated in the liver, but may promote the accumulation of lipids in the liver and further damage the liver function; and these drugs need to be taken for a long time and are expensive. Therefore, it is very necessary to actively search for drugs with liver protection, blood lipid lowering and anti-fatty liver functions.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供本发明化合物MAGLZ-Ⅱ-11在制备预防或治疗脂肪性肝病药物中的用途。The purpose of the present invention is to provide the use of the compound MAGLZ-II-11 of the present invention in the preparation of a medicament for preventing or treating fatty liver disease.
研究发现，本发明的MAGLZ-Ⅱ-11显著降低非酒精性脂肪肝病体重、肝指数，降低血清谷丙转氨酶(ALT)、谷草转氨酶(AST)水平，降低肝匀浆游离脂肪酸(FFA)、甘油三酯(TG)水平，具有显著的治疗非酒精性脂肪肝病的作用，其治疗效果好、安全性高。The study found that MAGLZ-II-11 of the present invention can significantly reduce the body weight and liver index of non-alcoholic fatty liver disease, reduce serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduce liver homogenate free fatty acid (FFA), glycerol. Triester (TG) level has a significant effect on the treatment of non-alcoholic fatty liver disease, and its therapeutic effect is good and the safety is high.
本发明MAGLZ-Ⅱ-11对于酒精性脂肪肝具有显著的治疗效果，能够降低血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、甘油三酯(TG)含量，具有显著的降脂保肝作用。The MAGLZ-II-11 of the present invention has a significant therapeutic effect on alcoholic fatty liver, can reduce serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) content, Has significant lipid-lowering and hepatoprotective effects.
本发明的MAGLZ-Ⅱ-11，结构式如下：MAGLZ-II-11 of the present invention has the following structural formula:
在一个方面，本申请提供了本发明化合物MAGLZ-Ⅱ-11用于预防或治疗脂肪性肝病药物中的用途，所述脂肪性肝病为非酒精性脂肪肝病或酒精性肝病。In one aspect, the present application provides the use of the compound MAGLZ-II-11 of the present invention for preventing or treating fatty liver disease, wherein the fatty liver disease is non-alcoholic fatty liver disease or alcoholic liver disease.
在一个实施方式中，所述非酒精性脂肪肝病为非酒精性脂肪肝、非酒精性脂肪性肝炎、非酒精性脂肪性肝纤维化或非酒精性脂肪性肝硬化。In one embodiment, the non-alcoholic fatty liver disease is non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver fibrosis or non-alcoholic fatty liver cirrhosis.
在一个实施方式中，所述酒精性肝病为酒精性肝炎、酒精性脂肪肝、酒精性肝纤维化或酒精性肝硬化。In one embodiment, the alcoholic liver disease is alcoholic hepatitis, alcoholic fatty liver disease, alcoholic liver fibrosis, or alcoholic liver cirrhosis.
实施例1研究了MAGLZ-Ⅱ-11对高脂饲料所致的大鼠非酒精性脂肪肝病的影响，结果显示，MAGLZ-Ⅱ-11显著降低体重、肝指数，降低血清谷丙转氨酶、谷草转氨酶水平，降低肝匀浆游离脂肪酸、甘油三酯水平，改善肝功能损伤，本发明MAGLZ-Ⅱ-11具有显著的治疗非酒精性脂肪肝病的作用。Example 1 The effect of MAGLZ-II-11 on non-alcoholic fatty liver disease in rats caused by high-fat diet was studied. The results showed that MAGLZ-II-11 significantly reduced body weight, liver index, serum alanine aminotransferase and aspartate aminotransferase. The level of free fatty acid and triglyceride in liver homogenate can be reduced, and the liver function damage can be improved. The MAGLZ-II-11 of the present invention has a significant effect on treating non-alcoholic fatty liver disease.
实施例2研究了MAGLZ-Ⅱ-11对高脂饲料/果糖模型小鼠非酒精性脂肪肝病的影响，结果显示，MAGLZ-Ⅱ-11降低血清丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、甘油三酯水平。Example 2 The effect of MAGLZ-II-11 on non-alcoholic fatty liver disease in high-fat diet/fructose model mice was studied. The results showed that MAGLZ-II-11 reduced serum alanine aminotransferase and aspartate aminotransferase. Enzyme and triglyceride levels.
实施例3表明MAGLZ-Ⅱ-11显著降低丙氨酸氨基转移酶、天门冬氨酸氨基转移酶水平，对大鼠酒精性脂肪肝肝功能有保护作用。MAGLZ-Ⅱ-11显著降低酒精性脂肪肝大鼠血清甘油三酯含量、总胆固醇含量和低密度脂蛋白胆固醇含量，提高血清高密度脂蛋白胆固醇含量，说明MAGLZ-Ⅱ-11具有调节血脂作用。Example 3 shows that MAGLZ-II-11 significantly reduces the levels of alanine aminotransferase and aspartate aminotransferase, and has a protective effect on the liver function of alcoholic fatty liver in rats. MAGLZ-Ⅱ-11 significantly decreased serum triglyceride, total cholesterol and low-density lipoprotein cholesterol content in alcoholic fatty liver rats, and increased serum high-density lipoprotein cholesterol content, indicating that MAGLZ-Ⅱ-11 has the effect of regulating blood lipids.
在又一个方面，本申请提供了本发明MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体体重和/或肝脏重量增加的产品中的应用。In yet another aspect, the present application provides the use of MAGLZ-II-11 of the present invention in the manufacture of a product for treating and/or preventing fatty liver disease from gaining body weight and/or liver weight.
在又一个方面，本申请提供了本发明MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体的血清中天门冬氨酸氨基转移酶和/或丙氨酸氨基转移酶增加的产品中的应用。In yet another aspect, the present application provides the increase of aspartate aminotransferase and/or alanine aminotransferase in the serum of MAGLZ-II-11 of the present invention in the preparation of treatment and/or prevention of fatty liver disease patients application in the product.
在又一个方面，本申请提供了本发明MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体的甘油三酯和/或游离脂肪酸增加的产品中的应用。In yet another aspect, the present application provides the use of MAGLZ-II-11 of the present invention in the manufacture of a product for treating and/or preventing increased triglycerides and/or free fatty acids in fatty liver disease-affected subjects.
在一个实施方式中，所述产品为保健品或药物。In one embodiment, the product is a nutraceutical or a drug.
在一个实施方式中，所述治疗和/或预防脂肪性肝病的产品为药物，所述药物中包括MAGLZ-Ⅱ-11与药学上可接受的辅料。In one embodiment, the product for treating and/or preventing fatty liver disease is a medicine, and the medicine includes MAGLZ-II-11 and pharmaceutically acceptable excipients.
在一个实施方式中，所述治疗和/或预防脂肪性肝病的药物包括各种可接受的剂型。In one embodiment, the medicament for treating and/or preventing fatty liver disease includes various acceptable dosage forms.
本发明的MAGLZ-Ⅱ-11的剂型没有特殊限制，例如可以是口服剂型或注射剂型。所述口服剂型可以是液体剂型，也可以是固体剂型。所述口服剂型选自硬胶囊、软胶囊、缓控释放胶囊、压片、糖衣片、粉剂、颗粒剂、滴丸、水蜜丸、糖浆或口服液；所述注射剂型选自溶液型、混悬液型、乳浊液型或冻干粉。The dosage form of MAGLZ-II-11 of the present invention is not particularly limited, for example, it may be an oral dosage form or an injection dosage form. The oral dosage form can be a liquid dosage form or a solid dosage form. The oral dosage form is selected from hard capsules, soft capsules, slow-release capsules, compressed tablets, sugar-coated tablets, powders, granules, dropping pills, honeydew pills, syrup or oral liquid; the injection dosage form is selected from solution type, suspension Liquid, emulsion or lyophilized powder.
所述用于预防和/或治疗脂肪性肝病的MAGLZ-Ⅱ-11的给药方式可以为口服、滴注或注射。The administration mode of MAGLZ-II-11 for preventing and/or treating fatty liver disease can be oral, drip or injection.
制备口服用固体制剂时，可以在向主药中加入赋形剂以及视需要而定的粘合剂、崩解剂、滑润剂、着色剂、矫味剂等后，按照常规方法制成片剂、包衣片剂、颗粒剂、细粒剂、散剂、胶囊剂等。When preparing a solid preparation for oral use, after adding an excipient and optionally a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. to the main drug, the tablet can be prepared according to a conventional method. , coated tablets, granules, fine granules, powders, capsules, etc.
作为赋形剂，可选自乳糖、玉米淀粉、葡萄糖、山梨糖醇、结晶纤维素、二氧化硅中的一种或几种。As an excipient, it can be selected from one or more of lactose, corn starch, glucose, sorbitol, crystalline cellulose and silicon dioxide.
作为粘合剂，可选自聚乙烯醇、乙基纤维素、甲基纤维素、阿拉伯胶、羟基丙基纤维素、羟基丙基甲基纤维素中的一种或几种。As the binder, it can be selected from one or more of polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.
作为滑润剂，可选自硬脂酸镁、滑石、二氧化硅中的一种或几种。As the lubricant, one or more of magnesium stearate, talc and silicon dioxide can be selected.
作为矫味剂，可使用可可粉、薄荷脑、芳香酸、薄荷油、龙脑、桂皮粉中的一种或几种。As a flavoring agent, one or more of cocoa powder, menthol, aromatic acid, peppermint oil, borneol and cinnamon powder can be used.
当然，也可以在上述片剂、颗粒剂上包覆糖衣、明胶衣、以及其它的必要外衣。Of course, the above-mentioned tablets and granules can also be coated with sugar coating, gelatin coating, and other necessary outer coatings.
制备注射剂时，可以根据需要向主药中添加pH调节剂、缓冲剂、悬助剂、增溶剂、稳定剂、等渗剂、防腐剂等，再按照常规方法制成静脉、皮下、肌肉内注射剂。此时，也可以根据需要，利用常规方法制成冷冻干燥物。When preparing injections, pH adjusters, buffers, suspending aids, solubilizers, stabilizers, isotonic agents, preservatives, etc. can be added to the main drug as required, and then intravenous, subcutaneous, and intramuscular injections can be prepared according to conventional methods. . At this time, if necessary, a freeze-dried product can be prepared by a conventional method.
作为悬助剂，可选自甲基纤维素、吐温80、羟基乙基纤维素、阿拉伯胶、羧甲基纤维素钠、聚氧乙烯山梨糖醇单月桂酸盐中的一种或几种。As a suspending aid, it can be selected from one or more of methyl cellulose, Tween 80, hydroxyethyl cellulose, gum arabic, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate .
作为增溶剂，可选自聚氧化乙烯氢化蓖麻油、吐温80、烟酰胺、聚氧乙烯山梨糖醇单月桂酸盐、聚乙二醇、蓖麻油脂肪酸乙酯中的一种或几种。As the solubilizer, it can be selected from one or more of polyoxyethylene hydrogenated castor oil, Tween 80, nicotinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol, and castor oil fatty acid ethyl ester.
另外，作为稳定剂，可选自亚硫酸钠、偏亚硫酸钠中的一种或几种；作为防腐剂，可选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、山梨酸、苯酚、甲酚、氯甲酚中的一种或几种。In addition, as a stabilizer, it can be selected from one or more of sodium sulfite and sodium metabisulfite; as a preservative, it can be selected from methylparaben, ethylparaben, sorbic acid, phenol, cresol, One or more of chlorocresol.
将本发明的MAGLZ-Ⅱ-11施用于对象，所述对象可以是哺乳动物，例如可以是人、大鼠、兔、羊、猪、牛、猫、狗、猴等，优选为人。The MAGLZ-II-11 of the present invention is administered to a subject, which may be a mammal, such as a human, a rat, a rabbit, a sheep, a pig, a cow, a cat, a dog, a monkey, etc., preferably a human.
上述药物制剂的制备方法均可采用本领域技术人员制备该种剂型常规使用制备方法制得。上述药物制剂中，每一制剂单位中含有本发明化合物的含量为0.001mg～50mg。The preparation methods of the above-mentioned pharmaceutical preparations can be prepared by those skilled in the art by conventional preparation methods for preparing such dosage forms. In the above pharmaceutical preparation, the content of the compound of the present invention contained in each preparation unit is 0.001 mg to 50 mg.
本发明MAGLZ-Ⅱ-11对于非酒精性脂肪肝病具有显著的治疗效果，能够显著降低体重、肝指数，降低血清ALT、AST水平，降低肝匀浆FFA、TG水平，改善肝功能损伤，本发明的MAGLZ-Ⅱ-11具有显著的治疗非酒精性脂肪肝病的作用。MAGLZ-Ⅱ-11在预防或治疗非酒精性脂肪肝病方面具有很好的开发应用价值。本发明MAGLZ-Ⅱ-11对于酒精性脂肪肝具有显著的治疗效果，能够降低ALT、AST，降低TG含量、TC含量和LDL-C含量，提高血清HDL-C含量，具有显著的降脂保肝作用。The MAGLZ-II-11 of the present invention has a significant therapeutic effect on non-alcoholic fatty liver disease, and can significantly reduce body weight, liver index, serum ALT and AST levels, and liver homogenate FFA and TG levels, and improve liver function damage. MAGLZ-II-11 has a significant effect on the treatment of non-alcoholic fatty liver disease. MAGLZ-Ⅱ-11 has good development and application value in the prevention or treatment of non-alcoholic fatty liver disease. The MAGLZ-II-11 of the present invention has a significant therapeutic effect on alcoholic fatty liver, can reduce ALT, AST, reduce TG content, TC content and LDL-C content, increase serum HDL-C content, and has significant lipid-lowering and liver-protecting effects effect.
图1实施例2各组的肝病理切片图。Fig. 1 The liver pathological sections of each group in Example 2.
为了使本领域技术人员充分了解本发明，以下通过具体的实施例进一步说明本发明，但本领域技术人员应该知晓，本发明实施例并不以任何方式限制本发明。In order for those skilled in the art to fully understand the present invention, the present invention is further described below through specific embodiments, but those skilled in the art should know that the embodiments of the present invention do not limit the present invention in any way.
以下实施例中，化合物MAGLZ-Ⅱ-2、MAGLZ-Ⅱ-10、MAGLZ-Ⅱ-11、MAGLZ-Ⅱ-17按照申请号为201910836454.5的发明专利中的方法制备得到。In the following examples, compounds MAGLZ-II-2, MAGLZ-II-10, MAGLZ-II-11, and MAGLZ-II-17 were prepared according to the methods in the invention patent with the application number of 201910836454.5.
实施例1 MAGLZ-Ⅱ-11对大鼠非酒精性脂肪肝病模型作用的实验研究Example 1 Experimental study on the effect of MAGLZ-II-11 on rat model of non-alcoholic fatty liver disease
SD大鼠，体重140-180g，雄性，72只，随机分为9组，即空白组、模型组、JZL184组、MAGLZ-Ⅱ-2组、MAGLZ-Ⅱ-10组、MAGLZ-Ⅱ-17组、MAGLZ-Ⅱ-11低剂量组、MAGLZ-Ⅱ-11中剂量组、MAGLZ-Ⅱ-11高剂量组。SD rats, weighing 140-180g, male, 72, were randomly divided into 9 groups, namely blank group, model group, JZL184 group, MAGLZ-Ⅱ-2 group, MAGLZ-Ⅱ-10 group, MAGLZ-Ⅱ-17 group , MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
常规饲养1W后，除空白对照组予基础饲料外，其余各组均饲以高脂饲料(84％基础饲料+10％猪油+5％蛋黄粉+1％胆固醇)。每周称1次体重，并相应调整给药量。After 1w of conventional feeding, except the blank control group which was given basic feed, the other groups were fed with high-fat feed (84% basic feed + 10% lard + 5% egg yolk powder + 1% cholesterol). Weigh the body weight once a week and adjust the dosage accordingly.
动物给药如下：Animals were dosed as follows:
于实验造模第7周结束时处死各组动物。隔夜禁食，次日以2％戊巴比妥钠溶液1mL/kg体重腹腔内注射麻醉后，迅速取出肝脏称肝湿重，并取肝左叶0.1cm×0.1cm×0.6cm标本2～4块，经戊二醛锷酸固定，然后取同部位1块0.5cm×1cm×0.3cm组织1块置于10％磷酸缓冲甲醛液中固定。Animals in each group were sacrificed at the end of the seventh week of experimental modeling. Fasting overnight, the next day after intraperitoneal injection of 2% pentobarbital sodium solution 1 mL/kg body weight for anesthesia, the liver was quickly taken out and weighed, and 0.1cm×0.1cm×0.6cm specimens from the left hepatic lobe were taken for 2-4 The block was fixed with glutaraldehyde acid, and then a 0.5cm×1cm×0.3cm piece of tissue was taken from the same site and fixed in 10% phosphate buffered formaldehyde solution.
检测血清ALT、AST，肝匀浆TG、FFA含量。Serum ALT, AST, liver homogenate TG, FFA content were detected.
结果result
(1)各组大鼠腹腔解剖所见，肝湿重、肝指数的变化(1) Changes of liver wet weight and liver index in abdominal cavity anatomy of rats in each group
模型组大鼠腹腔肥大，脂肪组织丰富，肝体积增大明显，包膜紧张，呈砖红色，切面油腻感，呈典型脂肪肝外观；MAGLZ-Ⅱ-11各组大鼠腹腔脂肪组织较模型组含量少，肝脏体积稍大、偏黄色，部分肝脏切面有油腻感。The abdominal cavity of the rats in the model group was hypertrophic, with abundant adipose tissue, significantly increased liver volume, tight capsule, brick red, greasy cut surface, and typical appearance of fatty liver; The content is small, the liver volume is slightly larger and yellowish, and part of the liver section has a greasy feeling.
各组大鼠体重、肝指数的变化见表1。The changes of body weight and liver index of rats in each group are shown in Table 1.
表1各组大鼠体重与肝指数的变化
Table 1 Changes of body weight and liver index of rats in each group
与模型组比较，*P<0.05，**P<0.01，***P<0.001；Compared with the model group, *P<0.05, **P<0.01, ***P<0.001;
与JZL184组比较，
ΩP<0.05，
ΩΩP<0.01。
Compared with the JZL184 group, Ω P<0.05, ΩΩ P<0.01.
表1显示，MAGLZ-Ⅱ-11各组的体重与肝指数明显低于模型组，MAGLZ-Ⅱ-11各组与模型组相比，体重、肝指数有显著性差异。Table 1 shows that the body weight and liver index of each MAGLZ-II-11 group were significantly lower than those of the model group. Compared with the model group, the body weight and liver index of each MAGLZ-II-11 group were significantly different.
与JZL184相比，MAGLZ-Ⅱ-11中、高剂量组体重与肝指数降低，具有显著性差异。Compared with JZL184, the body weight and liver index of MAGLZ-II-11 middle and high dose groups decreased, and there was a significant difference.
(2)各组大鼠血清肝功能ALT、AST及肝匀浆FFA、TG的变化(2) Changes of serum liver function ALT, AST and liver homogenate FFA and TG of rats in each group
表2显示，造模各组均出现不同程度的ALT、AST活性升高。Table 2 shows that the activities of ALT and AST increased in different degrees in each model group.
MAGLZ-Ⅱ-11各组与模型组ALT、AST的水平比较，有不同程度的降低，差异有显著性统计学意义。Compared with the model group, the levels of ALT and AST in each MAGLZ-Ⅱ-11 group were decreased in different degrees, and the difference was statistically significant.
与JZL184相比，MAGLZ-Ⅱ-11中、高剂量组ALT、AST的水平降低，具有显著性差异。Compared with JZL184, the levels of ALT and AST in MAGLZ-II-11 middle and high dose groups were decreased, and there was a significant difference.
肝匀浆FFA、TG以模型组最高、空白组最低。The FFA and TG of liver homogenate were the highest in the model group and the lowest in the blank group.
MAGLZ-Ⅱ-11各组FFA、TG水平有不同程度的下降。The levels of FFA and TG in MAGLZ-Ⅱ-11 groups decreased in different degrees.
表2各组大鼠血清肝功能ALT、AST及肝匀浆FFA、TG的变化
Table 2 Changes of serum liver function ALT, AST and liver homogenate FFA and TG of rats in each group
与模型组比较，*P<0.05，**P<0.01，***P<0.001；Compared with the model group, *P<0.05, **P<0.01, ***P<0.001;
与JZL184组比较，
ΩP<0.05，
ΩΩP<0.01。
Compared with the JZL184 group, Ω P<0.05, ΩΩ P<0.01.
结果显示，MAGLZ-Ⅱ-11各组可显著降低体重、肝指数，降低血清ALT、AST水平，降低肝匀浆FFA、TG水平，肝功能损伤较轻，本发明的MAGLZ-Ⅱ-11具有显著的治疗非酒精性脂肪肝病的作用。The results show that each group of MAGLZ-II-11 can significantly reduce body weight, liver index, serum ALT and AST levels, and liver homogenate FFA and TG levels, and the liver function damage is relatively mild. MAGLZ-II-11 of the present invention has significant role in the treatment of nonalcoholic fatty liver disease.
实施例2 MAGLZ-Ⅱ-11对高脂饲料/果糖模型小鼠非酒精性脂肪肝病模型作用的实验研究Example 2 Experimental study on the effect of MAGLZ-II-11 on high-fat diet/fructose model mice model of non-alcoholic fatty liver disease
8周大的C57BL/6N小鼠，64只，新环境适应一周后，分为8组，正常组、模型组、MAGLZ-Ⅱ-2组、MAGLZ-Ⅱ-10组、MAGLZ-Ⅱ-17组、MAGLZ-Ⅱ-11低剂量组、MAGLZ-Ⅱ-11中剂量组、MAGLZ-Ⅱ-11高剂量组。8-week-old C57BL/6N mice, 64 mice, were divided into 8 groups after one week of adaptation to the new environment, normal group, model group, MAGLZ-Ⅱ-2 group, MAGLZ-Ⅱ-10 group, MAGLZ-Ⅱ-17 group , MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
正常组小鼠喂食正常饲料，模型组小鼠和给药组小鼠喂食高脂饲料(HFD)八个周。The mice in the normal group were fed with normal chow, and the mice in the model group and the mice in the administration group were fed with high-fat diet (HFD) for eight weeks.
正常对照组给与正常饮用水和正常饲料，模型组小鼠和给药组小鼠给与高果糖和高葡萄糖饮用水(23.1g果糖和18.9g葡萄糖加到1L水里)并继续给与高脂饲料8个周后。The normal control group was given normal drinking water and normal diet, and the mice in the model group and the mice in the administration group were given high-fructose and high-glucose drinking water (23.1g fructose and 18.9g glucose were added to 1L of water) and continued to be given high-fructose and high-glucose drinking water. After 8 weeks of fat diet.
喂食HFD两周后，对给药组小鼠连续14天每天给药一次。After being fed with HFD for two weeks, the mice in the administration group were administered once a day for 14 consecutive days.
自造模第1天起，除空白组、模型组外，各组分别灌服0.5％羧甲基纤维素钠及相应药物，各组给药如下：From the first day of modeling, except for the blank group and the model group, each group was given 0.5% sodium carboxymethyl cellulose and corresponding drugs respectively. The administration of each group was as follows:
MAGLZ-Ⅱ-2组:16mg/kg MAGLZ-Ⅱ-2；MAGLZ-Ⅱ-2 group: 16mg/kg MAGLZ-Ⅱ-2;
MAGLZ-Ⅱ-10组:16mg/kg MAGLZ-Ⅱ-10；MAGLZ-Ⅱ-10 group: 16mg/kg MAGLZ-Ⅱ-10;
MAGLZ-Ⅱ-17组:16mg/kg MAGLZ-Ⅱ-17；MAGLZ-Ⅱ-17 group: 16mg/kg MAGLZ-Ⅱ-17;
MAGLZ-Ⅱ-11低剂量组:4mg/kg MAGLZ-Ⅱ-11；MAGLZ-Ⅱ-11 low-dose group: 4 mg/kg MAGLZ-Ⅱ-11;
MAGLZ-Ⅱ-11中剂量组:8mg/kg MAGLZ-Ⅱ-11；MAGLZ-Ⅱ-11 medium dose group: 8 mg/kg MAGLZ-Ⅱ-11;
MAGLZ-Ⅱ-11高剂量组:16mg/kg MAGLZ-Ⅱ-11。MAGLZ-II-11 high-dose group: 16 mg/kg MAGLZ-II-11.
14天后处死小鼠，并且称重小鼠体重和肝脏组织。Mice were sacrificed after 14 days, and mouse body weight and liver tissue were weighed.
用4％多聚甲醛固定各个肝脏的部分，通过苏木精和伊红(HE)染色分析肝脏组织学特征。收集并在液氮中冷冻其他组织以便使用，并收集血清以测量代谢 物参数。Sections of individual livers were fixed with 4% paraformaldehyde, and liver histological characteristics were analyzed by hematoxylin and eosin (HE) staining. Other tissues were collected and frozen in liquid nitrogen for use, and serum was collected to measure metabolite parameters.
实验结果：Experimental results:
(1)各组小鼠血清肝功能ALT、AST、TG的变化。MAGLZ-Ⅱ-11各组可以使ALT、AST、TG显著降低。结果见表3。(1) Changes of serum liver function ALT, AST and TG of mice in each group. MAGLZ-Ⅱ-11 groups can significantly reduce ALT, AST and TG. The results are shown in Table 3.
表3各组小鼠血清肝功能ALT、AST、TG的变化
Table 3 Changes of serum liver function ALT, AST and TG of mice in each group
△与模型组比较，
△P<0.05，
△△P<0.01，
△△△P<0.001。
△ Compared with the model group, △ P<0.05, △△ P<0.01, △△△ P<0.001.
(2)肝病理切片显示，模型组组肝中含有大量的脂肪粒、炎症坏死严重，而MAGLZ-Ⅱ-11各组脂肪粒较少、炎症较轻，见图1。(2) Liver pathological sections showed that the liver of the model group contained a large number of fat granules with severe inflammation and necrosis, while the MAGLZ-II-11 groups had fewer fat granules and milder inflammation, as shown in Figure 1.
实施例3 MAGLZ-Ⅱ-11对酒精性脂肪肝的作用Example 3 The effect of MAGLZ-II-11 on alcoholic fatty liver
SD大鼠，72只，体重180-220g，雌雄各半，随机分为9组，即对照组、模型组、JZL184组、MAGLZ-Ⅱ-2组、MAGLZ-Ⅱ-10组、MAGLZ-Ⅱ-17组、MAGLZ-Ⅱ-11低剂量组、MAGLZ-Ⅱ-11中剂量组、MAGLZ-Ⅱ-11高剂量组。SD rats, 72, weighing 180-220g, half male and half male, were randomly divided into 9 groups, namely control group, model group, JZL184 group, MAGLZ-Ⅱ-2 group, MAGLZ-Ⅱ-10 group, MAGLZ-Ⅱ- 17 groups, MAGLZ-II-11 low-dose group, MAGLZ-II-11 medium-dose group, MAGLZ-II-11 high-dose group.
对照组灌胃给予生理盐水，饲普通饲料；其余大鼠自由饮用10％酒精及饲高营养饲料(普通饲料添加10％全脂奶粉、10％蛋黄粉、10％炼猪油等)6周后，分成模型组和各给药组，继续饲高营养饲料和饮用10％酒精4周，同时开始灌胃给予药物或蒸馏水4周。末次给药24小时后，眼眶放血，并分离血清，测血清肝功能；处死动物，制肝匀浆，测肝细胞血脂，肝脂质过氧化指标。The control group was given normal saline by gavage and fed with normal feed; the rest of the rats were given free access to 10% alcohol and fed high-nutrient feed (normal feed supplemented with 10% whole milk powder, 10% egg yolk powder, 10% refined lard, etc.) after 6 weeks , divided into model group and each administration group, continued to feed high-nutrition feed and drink 10% alcohol for 4 weeks, and at the same time began to give drugs or distilled water by gavage for 4 weeks. 24 hours after the last administration, the orbits were bled, the serum was separated, and the serum liver function was measured; the animals were sacrificed, the liver homogenate was prepared, and the blood lipids of liver cells and the indexes of liver lipid peroxidation were measured.
动物给药如下：Animals were dosed as follows:
实验用酒：使用市售红星牌二锅头白酒，酒精度55％(V/V)，实验采用10％酒精浓度。Experimental wine: use the commercial Hongxing brand Erguotou liquor, the alcohol content is 55% (V/V), and the experiment uses 10% alcohol concentration.
使用TC、TG、ALT、AST、HDL-C、LDL-C试剂盒，测定含量。Use TC, TG, ALT, AST, HDL-C, LDL-C kits to determine the content.
结果result
(1)MAGLZ-Ⅱ-11对大鼠酒精性脂肪肝肝功能的影响，见表4。(1) The effect of MAGLZ-Ⅱ-11 on the liver function of alcoholic fatty liver in rats is shown in Table 4.
表4 MAGLZ-Ⅱ-11对酒精性脂肪肝大鼠肝功能的影响
Table 4 Effects of MAGLZ-Ⅱ-11 on liver function in alcoholic fatty liver rats
与对照组比较，
#P<0.015，
##P<0.01，
###P<0.001；
Compared with the control group, # P<0.015, ## P<0.01, ### P<0.001;
与模型组比较，*P<0.05，**P<0.01，***P<0.001；Compared with the model group, *P<0.05, **P<0.01, ***P<0.001;
与JZL184组比较，
ΩP<0.05，
ΩΩP<0.01。
Compared with the JZL184 group, Ω P<0.05, ΩΩ P<0.01.
结果表明，模型组与对照组比较，ALT明显升高，AST明显升高，说明模型出现肝脏酶学的改变，即肝细胞有变性或坏死发生。The results showed that compared with the control group, the ALT and AST of the model group were significantly increased, indicating that the model had changes in liver enzymes, that is, the degeneration or necrosis of liver cells occurred.
与模型组相比，MAGLZ-Ⅱ-11组可以显著降低升高的ALT、AST，说明MAGLZ-Ⅱ-11对大鼠酒精性脂肪肝肝功能有保护作用。Compared with the model group, the MAGLZ-Ⅱ-11 group can significantly reduce the elevated ALT and AST, indicating that MAGLZ-Ⅱ-11 has a protective effect on the liver function of alcoholic fatty liver in rats.
与JZL184相比，MAGLZ-Ⅱ-11中、高剂量组ALT、AST显著降低，具有显著性差异。Compared with JZL184, the ALT and AST of MAGLZ-II-11 middle and high dose groups were significantly decreased, and there was a significant difference.
(2)MAGLZ-Ⅱ-11对酒精性脂肪肝大鼠血清血脂的影响(2) Effects of MAGLZ-Ⅱ-11 on serum lipids in alcoholic fatty liver rats
表5 MAGLZ-Ⅱ-11对酒精性脂肪肝大鼠血脂的影响
Table 5 Effects of MAGLZ-Ⅱ-11 on blood lipids in alcoholic fatty liver rats
与对照组比较，
#P<0.015，
##P<0.01，
###P<0.001；
Compared with the control group, # P<0.015, ## P<0.01, ### P<0.001;
与模型组比较，*P<0.05，**P<0.01，***P<0.001；Compared with the model group, *P<0.05, **P<0.01, ***P<0.001;
与JZL184组比较，
ΩP<0.05，
ΩΩP<0.01。
Compared with the JZL184 group, Ω P<0.05, ΩΩ P<0.01.
表5结果表明MAGLZ-Ⅱ-11能显著降低酒精性脂肪肝大鼠血清TG含量、TC含量和LDL-C含量，提高血清HDL-C含量，说明MAGLZ-Ⅱ-11具有调节血脂作用。The results in Table 5 show that MAGLZ-II-11 can significantly reduce serum TG, TC and LDL-C levels in alcoholic fatty liver rats, and increase serum HDL-C levels, indicating that MAGLZ-II-11 has the effect of regulating blood lipids.
与JZL184相比，MAGLZ-Ⅱ-11高剂量组可显著降低酒精性脂肪肝大鼠血清TG含量、TC含量和LDL-C含量，提高血清HDL-C含量，具有显著性差异。Compared with JZL184, MAGLZ-Ⅱ-11 high-dose group can significantly reduce the serum TG, TC and LDL-C contents in alcoholic fatty liver rats, and increase the serum HDL-C contents, with significant difference.
以上结果表明MAGLZ-Ⅱ-11具有明显的保肝、降脂作用，可有效控制和消除因长期饮酒过量导致的酒精性脂肪肝。The above results show that MAGLZ-Ⅱ-11 has obvious hepatoprotective and lipid-lowering effects, and can effectively control and eliminate alcoholic fatty liver caused by long-term excessive drinking.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are more specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.
Claims (10)
- MAGLZ-Ⅱ-11在制备预防和/或治疗脂肪性肝病药物中的用途。Use of MAGLZ-II-11 in the preparation of a medicament for preventing and/or treating fatty liver disease.
- 如权利要求1所述的用途，其特征在于所述的脂肪性肝病是非酒精性脂肪肝病或酒精性肝病。The use according to claim 1, wherein the fatty liver disease is non-alcoholic fatty liver disease or alcoholic liver disease.
- 如权利要求2所述的用途，其特征在于所述的非酒精性脂肪肝病是非酒精性脂肪肝、非酒精性脂肪性肝炎、非酒精性脂肪性肝纤维化或非酒精性脂肪性肝硬化。The use according to claim 2, wherein the non-alcoholic fatty liver disease is non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver fibrosis or non-alcoholic fatty liver cirrhosis.
- 如权利要求2所述的用途，其特征在于所述的酒精性肝病是酒精性肝炎、酒精性脂肪肝、酒精性肝纤维化或酒精性肝硬化。The use according to claim 2, wherein the alcoholic liver disease is alcoholic hepatitis, alcoholic fatty liver, alcoholic liver fibrosis or alcoholic liver cirrhosis.
- MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体体重和/或肝脏重量增加的药物中的应用。Application of MAGLZ-II-11 in the preparation of a medicament for treating and/or preventing the increase of body weight and/or liver weight in patients with fatty liver disease.
- MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体的血清中天冬氨酸氨基转移酶和/或丙氨酸氨基转移酶增加的药物中的应用。Application of MAGLZ-II-11 in the preparation of a medicament for treating and/or preventing the increase of aspartate aminotransferase and/or alanine aminotransferase in the serum of fatty liver disease patients.
- MAGLZ-Ⅱ-11在制备治疗和/或预防脂肪性肝病患病机体的甘油三酯和/或游离脂肪酸增加的药物中的应用。Application of MAGLZ-II-11 in the preparation of a medicament for treating and/or preventing the increase of triglycerides and/or free fatty acids in fatty liver disease patients.
- 如权利要求1-7任一项所述的用途，其特征在于MAGLZ-Ⅱ-11的剂型是口服剂型或注射剂型。The use according to any one of claims 1-7, wherein the dosage form of MAGLZ-II-11 is an oral dosage form or an injection dosage form.
- 如权利要求8所述的用途，其特征在于，所述口服剂型选自硬胶囊、软胶囊、缓控释放胶囊、压片、糖衣片、粉剂、颗粒剂、滴丸、水蜜丸、糖浆或口服液；所述注射剂型选自溶液型、混悬液型、乳浊液型或冻干粉。The use according to claim 8, wherein the oral dosage form is selected from the group consisting of hard capsules, soft capsules, slow-release capsules, compressed tablets, sugar-coated tablets, powders, granules, dripping pills, honeydew pills, syrup or oral administration The injection dosage form is selected from solution type, suspension type, emulsion type or freeze-dried powder.
- 如权利要求9所述的用途，其特征在于所述药物制剂，每一制剂单位中MAGLZ-Ⅱ-11含量为0.001mg-50mg。The use according to claim 9, characterized in that in the pharmaceutical preparation, the content of MAGLZ-II-11 in each preparation unit is 0.001 mg-50 mg.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011529150 | 2020-12-22 | ||
| CN202011529150.3 | 2020-12-22 | ||
| CN202011529146 | 2020-12-22 | ||
| CN202011529146.7 | 2020-12-22 |
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| PCT/CN2021/140422 WO2022135461A1 (en) | 2020-12-22 | 2021-12-22 | Use of magl inhibitor in preparation of medicament for preventing or treating fatty liver diseases |
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| AU2004209505A1 (en) * | 2003-02-10 | 2004-08-19 | Banyu Pharmaceutical Co., Ltd. | Melanin-concentrating hormone receptor antagonists containing piperidine derivatives as the active ingredient |
| WO2020016710A1 (en) * | 2018-07-19 | 2020-01-23 | Pfizer Inc. | Heterocyclic spiro compounds as magl inhibitors |
| CN111518020A (en) * | 2019-02-01 | 2020-08-11 | 鲁南制药集团股份有限公司 | MAGL inhibitor and preparation method and application thereof |
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