WO2019227764A1 - 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途 - Google Patents

一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途 Download PDF

Info

Publication number
WO2019227764A1
WO2019227764A1 PCT/CN2018/104577 CN2018104577W WO2019227764A1 WO 2019227764 A1 WO2019227764 A1 WO 2019227764A1 CN 2018104577 W CN2018104577 W CN 2018104577W WO 2019227764 A1 WO2019227764 A1 WO 2019227764A1
Authority
WO
WIPO (PCT)
Prior art keywords
mln4924
obesity
mice
mln
diabetes
Prior art date
Application number
PCT/CN2018/104577
Other languages
English (en)
French (fr)
Inventor
饶枫
Original Assignee
南方科技大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南方科技大学 filed Critical 南方科技大学
Publication of WO2019227764A1 publication Critical patent/WO2019227764A1/zh

Links

Images

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones

Definitions

  • the present application relates to the field of pharmaceutical applications, in particular to a new use of MLN4924 in the preparation of treatment for diabetes and obesity, and in particular to a new use of a ubiquitin ligase targeting drug MLN4924 in the preparation of treatment for diabetes and / or obesity.
  • Type I diabetes is mainly due to genetic factors that prevent patients from producing sufficient insulin
  • Type II diabetes accounts for 90% of the total number of patients, mainly due to the inability of the body to effectively use insulin, which is often accompanied by obesity and insulin resistance Subject.
  • diabetes is the disease with the largest number of patients, accounting for 1/10 of the total adult population, up to 110 million people. What is more serious is that nearly half of Chinese adults are in the pre-obesity / diabetes stage, which brings the risk of suffering from other diseases such as type 2 diabetes and cardiovascular disease, and has a serious impact on human health and socioeconomics.
  • Current treatments include increasing insulin secretion (e.g., sulfonylureas), increasing cell sensitivity to insulin (e.g., thiazolidinediones), and reducing the rate of glucose absorption in the gastrointestinal tract (e.g., ⁇ -glucosidase inhibition ⁇ ). Clinical results prove that these drugs have limited effectiveness.
  • MLN4924 is a potent and selective NEDD8-activating enzyme (NAE) inhibitor with IC50 value of 4nM.
  • NAE NEDD8-activating enzyme
  • HCT-116 cells MLN4924 caused a reduction in Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, thereby inhibiting CRL-ubiquitination-mediated protein degradation (such as CDT1 protein) and CDT1 protein accumulation Can cause cell cycle defects.
  • CRL-ubiquitination-mediated protein degradation such as CDT1 protein
  • CDT1 protein accumulation Can cause cell cycle defects.
  • HCT-116 xenograft mice MLN4924 significantly inhibited tumor growth at doses of 30 mg / kg and 60 mg / kg, and these doses were well tolerated.
  • MLN4924 also has antitumor activity in H522 and Calu-6 lung cancer xenograft mice.
  • CN105708839A discloses the application of the small molecule inhibitor MLN4924 in the preparation of a medicament for inhibiting bleomycin-induced pulmonary fibrosis, and also discloses the small molecule inhibitor Application of MLN4924 in the preparation of medicament for the inflammatory process of early pulmonary fibrosis induced by bleomycin.
  • CN 103520163 A discloses the application of tumor suppressor MLN4924 in the preparation of antiviral drugs.
  • no study has been conducted on MLN4924 for the treatment of diabetes and obesity.
  • this application provides a new use of MLN4924 in the preparation of medicines for treating diabetes and / or obesity.
  • This application provides a new approach and option for the treatment of diabetes and obesity.
  • the application provides the use of an inhibitor MLN4924 in the manufacture of a medicament for the treatment of diabetes and / or obesity.
  • the MLN4924 has a structural formula as shown in Formula I below, a molecular formula of C 21 H 25 N 5 O 4 S and a molecular weight of 443.52. It is a small molecule inhibitor of NEDD8-activating enzyme (NAE). Formation of the NAE-MLN4924 complex inhibits NAE activity and inhibits ubiquitinated degradation of a class of proteins that are partially dependent on Cullin-Ring E31igase (CRL).
  • NAE NEDD8-activating enzyme
  • the MLN4924 inhibitor targets ubiquitin ligase, thereby inhibiting ubiquitin-like modification, thereby inhibiting insulin secretion and achieving the purpose of treating diabetes and obesity.
  • the research in this application shows that MLN4924 can significantly reduce the weight of mice in mice, especially for high-fat-fed mice, and the dosage of 5-20mg / kg can significantly reduce the weight of obesity.
  • the tree's insulin secretion and glucose content can play a significant role.
  • the use of the medicament for the preparation of a pharmaceutical composition for the treatment of diabetes and / or obesity is possible.
  • the medicine can also be used in combination with other medicines or other means to further treat diabetes and obesity.
  • the application provides an inhibitor MLN4924 for use in preparing a medicament for inhibiting insulin secretion.
  • the inventors have discovered that excessive secretion of insulin can induce insulin resistance, thereby feedback-stimulating insulin secretion and entering a vicious cycle. Therefore, attenuating insulin secretion can effectively reduce obesity-induced insulin resistance and hyperglycemia, indicating that inhibition of protein ubiquitination can effectively inhibit insulin secretion and obesity, and the use of MLN4924 can achieve the effect of treating obesity and diabetes.
  • the study of this application found that the concentration of MLN4924 at 500nM-1mM can achieve the function of inhibiting insulin secretion.
  • the use of the medicament for the preparation of a pharmaceutical composition that inhibits insulin secretion is not limited.
  • the drug may also be used in combination with other drugs or other means to further inhibit insulin secretion.
  • the present application provides the use of an inhibitor MLN4924 in the preparation of a medicament targeting a ubiquitin ligase.
  • the use of the medicament for the preparation of a pharmaceutical composition targeting a ubiquitin ligase is intended to be used for the preparation of a pharmaceutical composition targeting a ubiquitin ligase.
  • the drug can also be used in combination with other drugs or other means, so as to more precisely target ubiquitin ligase.
  • the medicament also includes a pharmaceutically acceptable excipient.
  • the auxiliary material is any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, and a filler.
  • the present application finds that excessive secretion of insulin can induce insulin resistance, thereby feeding back stimulation of insulin secretion and entering a vicious circle, therefore, weakening insulin secretion or effectively reducing obesity-induced insulin resistance and hyperglycemia;
  • the MLN4924 inhibitor can target ubiquitin ligase and inhibit ubiquitin-like modification, thereby inhibiting insulin and achieving the treatment of diabetes and obesity.
  • Figure 1 shows the effect of body weight of high-fat-fed mice in this application.
  • Group A normal chow diet (NCD) + injection (NCD vehicle);
  • group B normal diet + MLN4924 (NCD MLN 4924);
  • group C High fat diet (HFD) + injection (HFD vehicle);
  • group D high fat diet + MLN4924 (HFD MLN 4924);
  • Figure 2 shows epididymal white fat in mice treated with different diets and drugs.
  • group A normal diet + injection (NCD solvent);
  • group B normal diet + MLN4924 (NCD MLN 4924);
  • group C high-fat diet + Injection (HFD vehicle);
  • group D high-fat diet + MLN4924 (HFD MLN 4924);
  • Figure 3 shows the effect of MLN4924 on the insulin content in serum under the condition of eating or fasting.
  • Group A normal diet + injection (NCD solvent);
  • group B normal diet + MLN4924 (NCD MLN 4924);
  • group C high-fat diet + Injection (HFD vehicle);
  • group D high-fat diet + MLN4924 (HFD MLN 4924);
  • Figure 4 shows the effect of MLN4924 on glucose content in the state of eating or fasting, where group A: normal diet + injection (NCD solvent); group B: normal diet + MLN4924 (NCD MLN 4924); group C: high-fat diet + injection (HFD vehicle); Group D: High-fat diet + MLN4924 (HFD MLN 4924).
  • group A normal diet + injection (NCD solvent); group B: normal diet + MLN4924 (NCD MLN 4924); group C: high-fat diet + injection (HFD vehicle); Group D: High-fat diet + MLN4924 (HFD MLN 4924).
  • Figure 5 shows the effect of MLN4924 on the body weight of ob / ob obese / diabetic model mice in this application, where group A: injection (ob / ob vehicle); group B: MLN4924 drug treatment (ob / ob MLN 4924);
  • Figure 6 is a comparison of mouse inguinal white adipose tissue (IWAT) under different diets and drug treatments in this application, where group A: injection (ob / ob vehicle); group B: MLN4924 drug treatment (ob / ob MLN 4924);
  • Figure 7 shows the effect of MLN4924 on the insulin content in serum under the condition of eating or fasting, where group A: injection (ob / ob vehicle); group B: MLN4924 drug treatment (ob / ob MLN 4924);
  • Fig. 8 shows the effect of MLN4924 on blood glucose concentration in a fed or fasted state, where group A: injection (ob / ob vehicle); group B: MLN4924 drug treatment (ob / ob MLN 4924).
  • Experimental materials The sources of experimental materials are as follows, MLN4924: ApexBio, high-fat feed: Research Diets, Insulin Eliza kit: Crystal Chem, blood glucose meter and blood glucose test strips: Ankang.
  • mice C57 / B6 wild-type mice and Ob / ob mice were purchased from Nanjing University-Nanjing Institute of Biomedicine.
  • Example 1 Establishment of a mouse model of obesity and diabetes induced by a high-fat diet
  • the animal disease model is established by intraperitoneal or intravenous injection.
  • the specific steps are as follows:
  • mice (a total of 20) were divided into 4 groups, of which two groups (A and B) were fed with high fat, and the other two groups (C and D) were fed normally. Groups A and C were injected with MLN4924, respectively. Groups B and D were injected with a solvent, and body weight was measured every week for 10 weeks. The results are shown in Figure 1;
  • mice after 10 weeks of culture in step (1) were tested for insulin secretion and glucose content, and the results are shown in Figure 3-4;
  • mice in group A and C had significantly lower body weight than the mice in group B and D injected with the solvent, especially for mice fed with high fat.
  • the weight of the fed mice has a significant inhibitory effect, which can reduce the weight of the mice;
  • mice in groups A and C had significantly lower insulin secretion and glucose content compared to mice in groups B and D, especially for high fat-fed mice. More clearly, it can be seen that MLN4924 can significantly inhibit insulin secretion and glucose content in obese mice fed with high fat.
  • the animal disease model is established by intraperitoneal or intravenous injection.
  • the specific steps are as follows:
  • mice carry a lack of leptin gene and will overeat and cause obesity and diabetes.
  • mice (ob / ob) were divided into two groups, and the drug MLN4924 or solvent was injected, and the body weight was measured twice a week for 40 days. The results are shown in Figure 5;
  • mice after 40 days of culture in step (1) were tested for insulin secretion and glucose content. The results are shown in Figure 7-8;
  • mice after injecting MLN4924, compared with the solvent injection group, the mice have reduced inguinal white adipose tissue. It can be seen that MLN4924 can significantly reduce the epididymal white adipose tissue in high-fat-fed mice;
  • MLN4924 can significantly Inhibits Insulin Secretion and Glucose Content in High Fat-Fed Obese Mice
  • MLN4924 in addition to the effect of suppressing tumor growth, MLN4924 also has a significant inhibitory effect on diabetes and obesity symptoms.

Landscapes

  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本申请涉及一种抑制剂MLN4924在制备治疗糖尿病和肥胖的新用途，特别涉及一种泛素连接酶靶向药物MLN4924在制备治疗糖尿病和/或肥胖药物的新用途。本申请通过将抑制剂MLN4924作用于小鼠，发现MLN4924抑制剂可以靶向泛素连接酶，抑制类泛素化修饰，从而抑制胰岛素，实现糖尿病和肥胖的治疗。

Description

一种MLN4924在制备治疗糖尿病和/或肥胖药物的新用途 技术领域
本申请涉及药物应用领域，尤其涉及一种MLN4924在制备治疗糖尿病和肥胖的新用途，特别涉及一种泛素连接酶靶向药物MLN4924在制备治疗糖尿病和/或肥胖药物的新用途。
背景技术
国内外肥胖/糖尿病患者数量呈增加趋势。美国最新研究发现，在医疗手段大大提高的今天，人们的健康水平没有提高，主要原因就是肥胖/糖尿病的加重。糖尿主要有两种：I型糖尿病主要是由于遗传因素使患者体内无法生成足够的胰岛素；II型糖尿病占患者总数的90％，主要是由于身体无法有效利用胰岛素引起的，多伴随肥胖和胰岛素耐受。
在中国，糖尿病是患者最多的疾病，占成年人总数的1/10，高达1.1亿人。更为严重的是，近半数中国成年人处于肥胖/糖尿病前期，这带来罹患II型糖尿病和心血管病等其他疾病的风险，给人类健康和社会经济带来严重影响。当前治疗的方法包括增加胰岛素的分泌量(如磺脲类药物)，增加细胞对胰岛素的敏感性(如噻唑烷二酮类药物)和减少肠胃道吸收葡萄糖的速率(如α-葡萄糖苷酶抑制剂)。临床结果证明这些药物效果有限。
目前有一个新兴的“明星”药物——二甲双胍，双胍类药物可增强肌肉和脂肪组织对于葡萄糖的感受性，促使能量消耗，降低血糖和肥胖，但其有明显副作用且作用机制一直有争议。
MLN4924是一种有效的和选择性的NEDD8激活酶(NEDD8-activating enzyme，NAE)抑制剂，IC50值为4nM。在HCT-116细胞中，MLN4924导致 Ubc12-NEDD8硫酯和NEDD8-滞蛋白(cullin)缀合物的减少，从而抑制CRL-泛素化介导的蛋白降解(比如CDT1蛋白)，CDT1蛋白的积累会引起细胞周期缺陷。在HCT-116异种移植小鼠中，MLN4924以30mg/kg和60mg/kg的剂量显著抑制肿瘤生长，这些剂量的耐受性良好。在H522和Calu-6肺癌异种移植小鼠中，MLN4924也具有抗肿瘤活性。
不仅如此，现有技术中还公开了NLN4924在其他领域的应用，CN105708839A公开了小分子抑制剂MLN4924在制备抑制博来霉素诱导的肺纤维化的药物中的应用，还公开了小分子抑制剂MLN4924在制备博来霉素诱导的肺纤维化早期炎症过程的药物中的应用。CN 103520163 A公开了肿瘤抑制剂MLN4924在制备抗病毒药物中的应用。但目前尚无研究MLN4924用于治疗糖尿病和肥胖。
总的来说目前针对II型糖尿病的常见治疗方法和相关药物容易引发机体抵抗，效果有限，因此，研发治疗糖尿病的新靶点和新药物意义十分重大。
发明内容
针对现有技术的不足及实际的需求，本申请提供一种MLN4924在制备治疗糖尿病和/或肥胖药物的新用途。本申请为糖尿病和肥胖的治疗提供了一条新的途径和选择。
为达此目的，本申请采用以下技术方案：
一方面，本申请提供抑制剂MLN4924在制备治疗糖尿病和/或肥胖的药物中的用途。
所述MLN4924，其结构式如下式I所示，分子式为C 21H 25N 5O 4S，分子量为443.52，是NEDD8活化酶(NEDD8-activating enzyme，NAE)的小分子抑制剂，主要通过与NAE形成NAE-MLN4924复合物抑制NAE活性，抑制了部分依赖于 Cullin-Ring E31igase(CRL)介导的一类蛋白质的泛素化降解。
Figure PCTCN2018104577-appb-000001
本申请中，所述MLN4924抑制剂通过靶向泛素连接酶，从而抑制类泛素化修饰，从而能够抑制胰岛素过分泌，实现治疗糖尿病和肥胖的目的。
在一个具体的实施例中，本申请研究表明MLN4924在小鼠体内能够显著降低小鼠体重，尤其针对高脂喂养的小鼠尤其明显，且其用量在5-20mg/kg都能够显著降低肥胖小树的胰岛素分泌和葡萄糖含量，能够显著发挥作用。
根据本申请，所述药物用于制备治疗糖尿病和/或肥胖的药物组合物中的用途。
本申请中，所述药物还可以与其他药物或其他手段联合使用，从而进一步治疗糖尿病和肥胖。
第二方面，本申请提供一种抑制剂MLN4924在制备抑制胰岛素分泌的药物中的用途。
本申请中，发明人发现，胰岛素过量分泌能诱发胰岛素抵抗，从而反馈刺激胰岛素分泌，进入恶性循环。因此，减弱胰岛素分泌或能有效降低肥胖诱导的胰岛素抵抗和高血糖，表明抑制蛋白质类泛素化能有效抑制胰岛素分泌和肥 胖，利用MLN4924能达到治疗肥胖和糖尿病的效果。
在一个具体的实施例中，本申请研究发现，MLN4924的浓度在500nM-1mM就可以实现抑制胰岛素分泌的功能。
根据本申请，所述药物用于制备抑制胰岛素分泌的药物组合物中的用途。
本申请中，所述药物还可以与其他药物或其他手段联合使用，从而进一步抑制胰岛素分泌。
第三方面，本申请提供一种抑制剂MLN4924在制备靶向泛素连接酶的药物中的用途。
根据本申请，所述药物用于制备靶向泛素连接酶的药物组合物中的用途。
本申请中，所述药物还可以与其他药物或其他手段联合使用，从而更加精准靶向泛素连接酶。
根据本申请，所述药物还包括药学上可接受的辅料。
根据本申请，所述辅料为赋形剂、稀释剂、载体、调味剂、粘合剂和填充剂中的任意一种或至少两种的组合。
与现有技术相比，本申请具有如下有益效果：
(1)本申请发现胰岛素过量分泌能诱发胰岛素抵抗，从而反馈刺激胰岛素分泌，进入恶性循环，因此，减弱胰岛素分泌或能有效降低肥胖诱导的胰岛素抵抗和高血糖；
(2)本申请通过将抑制剂MLN4924作用于小鼠，发现MLN4924抑制剂可以靶向泛素连接酶，抑制类泛素化修饰，从而抑制胰岛素，实现糖尿病和肥胖的治疗。
附图说明
图1为本申请高脂喂养小鼠体重的影响，其中，A组：正常饮食(normal chow  diet，NCD)+注射剂(NCD溶媒)；B组：正常饮食+MLN4924(NCD  MLN4924)；C组：高脂饮食(high fat diet，HFD)+注射剂(HFD溶媒)；D组：高脂饮食+MLN4924(HFD  MLN4924)；
图2为不同饮食和药物处理下的小鼠附睾白色脂肪，其中，A组：正常饮食+注射剂(NCD溶媒)；B组：正常饮食+MLN4924(NCD  MLN4924)；C组：高脂饮食+注射剂(HFD溶媒)；D组：高脂饮食+MLN4924(HFD  MLN4924)；
图3为进食或者空腹状态下MLN4924对血清中胰岛素含量的影响，其中，A组：正常饮食+注射剂(NCD溶媒)；B组：正常饮食+MLN4924(NCD  MLN4924)；C组：高脂饮食+注射剂(HFD溶媒)；D组：高脂饮食+MLN4924(HFD  MLN4924)；
图4为进食或者空腹状态下MLN4924对葡萄糖含量的影响，其中，A组：正常饮食+注射剂(NCD溶媒)；B组：正常饮食+MLN4924(NCD  MLN4924)；C组：高脂饮食+注射剂(HFD溶媒)；D组：高脂饮食+MLN4924(HFD  MLN4924)。
图5为本申请MLN4924对ob/ob肥胖/糖尿病模型小鼠体重的影响，其中，A组：注射剂(ob/ob溶媒)；B组：MLN4924药物处理(ob/ob  MLN4924)；
图6为本申请不同饮食和药物处理下的小鼠腹股沟白色脂肪组织(inguinal white adipose tissue，IWAT)比较，其中，A组：注射剂(ob/ob溶媒)；B组：MLN4924药物处理(ob/ob  MLN4924)；
图7为进食或者空腹状态下MLN4924对血清中胰岛素含量的影响，其中，A组：注射剂(ob/ob溶媒)；B组：MLN4924药物处理(ob/ob  MLN4924)；
图8为进食或者空腹状态下MLN4924对血糖浓度的影响，其中，A组：注射剂(ob/ob溶媒)；B组：MLN4924药物处理(ob/ob  MLN4924)。
具体实施方式
为更进一步阐述本申请所采取的技术手段及其效果，以下结合附图并通过 具体实施方式来进一步说明本申请的技术方案，但本申请并非局限在实施例范围内。
实施本申请的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本申请没有特别限制内容。各实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York：Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另有说明，本说明书中使用的全部专业术语和科学用语的含义均与本申请所属技术领域的技术人员一般理解的含义相同。但如有冲突，以包含定义的本说明书为准。
实验材料：实验材料来源如下，MLN4924：ApexBio，高脂饲料：Research Diets，Insulin Eliza试剂盒：Crystal Chem，血糖仪及血糖试纸：拜安康。
实验动物：C57/B6野生型小鼠和Ob/ob小鼠购买自南京大学-南京生物医药研究院。
实施例1 高脂饮食诱导的肥胖及糖尿病小鼠模型建立
本实施例中，动物疾病模型的建立均采用腹腔或静脉注射给药的方式，具体步骤如下：
(1)将实验小鼠(共20只)均分为4组，其中两组(A和B)高脂喂养，另外两组(C和D)正常喂养，分别将A和C组注射MLN4924，B和D组注射溶剂，每周进行体重检测，共培养10周，结果如图1所示；
(2)将步骤(1)培养10周后的小鼠剖取附睾白色脂肪组织，进行比较，结果如图2所示；
(3)将步骤(1)培养10周后的小鼠进行胰岛素分泌和葡萄糖含量的检测，结果如图3-4所示；
从图1可以看出，A和C组小鼠在注射MLN4924后相比于注射溶剂的B和D组小鼠，体重明显下降，尤其针对高脂喂养小鼠更加明显，可见，MLN4924对高脂喂养的小鼠体重有明显抑制作用，能够减少小鼠体重；
从图2可以看出，A和C组小鼠在注射MLN4924后相比于注射溶剂的B和D组小鼠，小鼠体内的附睾白色脂肪组织减少，尤其针对高脂喂养小鼠更加明显(个体体重越大附睾白色脂肪组织越多)，可见，MLN4924能显著减少高脂喂养小鼠体内的附睾白色脂肪组织；
从图3和图4可以看出，A和C组小鼠在注射MLN4924后相比于注射溶剂的B和D组小鼠，胰岛素分泌量和葡萄糖含量都显著降低，尤其针对高脂喂养小鼠更加明显，可见，MLN4924能够显著的抑制高脂喂养的肥胖小鼠的胰岛素分泌和葡萄糖含量。
实施例2 瘦素基因缺失的ob/ob小鼠肥胖及糖尿病模型建立
本实施例中，动物疾病模型的建立均采用腹腔或静脉注射给药的方式，具体步骤如下：
(1)Ob/ob小鼠携带瘦素基因缺失，会过量饮食从而产生肥胖和糖尿病。本实验将小鼠(ob/ob)分为两组，分别注射药物MLN4924或溶剂，每周进行两次体重检测，共培养40天，结果如图5所示；
(2)将步骤(1)培养40天后的小鼠剖取腹股沟白色脂肪组织，进行比较，结果如图6所示；
(3)将步骤(1)培养40天后的小鼠进行胰岛素分泌和葡萄糖含量的检测，结果如图7-8所示；
从图5可以看出，ob/ob小鼠在注射MLN4924后相比于注射溶剂组小鼠，体重明显下降，尤其针对高脂喂养小鼠更加明显，可见，MLN4924对高脂喂养 的小鼠体重有明显抑制作用，能够减少小鼠体重；
从图6可以看出，小鼠在注射MLN4924后相比于注射溶剂组小鼠，小鼠体内的腹股沟白色脂肪组织减少，可见，MLN4924能显著减少高脂喂养小鼠体内的附睾白色脂肪组织；
从图7和图8可以看出，小鼠在注射MLN4924后相比于注射溶剂组小鼠，胰岛素分泌量和葡萄糖含量都显著降低，尤其针对高脂喂养小鼠更加明显，可见，MLN4924能够显著的抑制高脂喂养的肥胖小鼠的胰岛素分泌和葡萄糖含量。
综上所述，本申请研究结果表明MLN4924除了有抑制肿瘤生长的效果之外，针对糖尿病和肥胖症状也具有明显的抑制效果。
申请人声明，本申请通过上述实施例来说明本申请的详细方法，但本申请并不局限于上述详细方法，即不意味着本申请必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (8)

  1. 抑制剂MLN4924在制备治疗糖尿病和/或肥胖的药物中的用途。
  2. 根据权利要求1所述的用途，其中，所述药物用于制备治疗糖尿病和/或肥胖的药物组合物中的用途。
  3. 抑制剂MLN4924在制备抑制胰岛素分泌的药物中的用途。
  4. 根据权利要求3所述的用途，其中，所述药物用于制备抑制胰岛素分泌的药物组合物中的用途。
  5. 抑制剂MLN4924在制备靶向泛素连接酶的药物中的用途。
  6. 根据权利要求5所述的用途，其中，所述药物用于制备靶向泛素连接酶的药物组合物中的用途。
  7. 根据权利要求1-6中任一项所述的用途，其中，所述药物还包括药学上可接受的辅料。
  8. 根据权利要求7所述的用途，其中，所述辅料为赋形剂、稀释剂、载体、调味剂、粘合剂和填充剂中的任意一种或至少两种的组合。
PCT/CN2018/104577 2018-05-28 2018-09-07 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途 WO2019227764A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810521470 2018-05-28
CN201810521470.0 2018-05-28

Publications (1)

Publication Number Publication Date
WO2019227764A1 true WO2019227764A1 (zh) 2019-12-05

Family

ID=63470429

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/104577 WO2019227764A1 (zh) 2018-05-28 2018-09-07 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途

Country Status (2)

Country Link
CN (1) CN108524519A (zh)
WO (1) WO2019227764A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022056252A1 (en) * 2020-09-10 2022-03-17 The Board Of Regents Of The University Of Oklahoma Compositions and methods for treating hyperglycemia in type-2 diabetes

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108524519A (zh) * 2018-05-28 2018-09-14 南方科技大学 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途
CN111603459A (zh) * 2020-06-30 2020-09-01 南方科技大学 一种苏拉明类化合物在制备五磷酸肌醇激酶抑制剂中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108524519A (zh) * 2018-05-28 2018-09-14 南方科技大学 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101552493B1 (ko) * 2013-07-18 2015-09-11 서울대학교산학협력단 PPAR-ν의 네딜화 억제제를 포함하는 지방세포분화 억제용 조성물 및 그 용도

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108524519A (zh) * 2018-05-28 2018-09-14 南方科技大学 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PARK, ET AL.: "PPAR y neddylation essential for adipogenesis is a potential target for treating obesity", CELL DEATH AND DIFFERENTIATION, vol. 23, no. 8, 18 March 2016 (2016-03-18), pages 1296 - 1311, XP055657658 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022056252A1 (en) * 2020-09-10 2022-03-17 The Board Of Regents Of The University Of Oklahoma Compositions and methods for treating hyperglycemia in type-2 diabetes

Also Published As

Publication number Publication date
CN108524519A (zh) 2018-09-14

Similar Documents

Publication Publication Date Title
CN110200981A (zh) 五环三萜皂苷的医药用途及其药物组合物
WO2019227764A1 (zh) 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途
EP3193907B1 (en) Method of treating prader-willi syndrome
Furukawa et al. The effectiveness of dapagliflozin for sleep-disordered breathing among Japanese patients with obesity and type 2 diabetes mellitus
US20220054459A1 (en) Prophylactic and therapeutic drug for nonalcoholic fatty liver disease
JPH10510241A (ja) Ｉｉ型糖尿病治療薬剤としてのケトコナゾール、および、その関連物質の使用法
EP3132798B1 (en) Use of composition containing iron (ii) amino acid chelate in preparing drug for regulating and controlling fat metabolism
CN115803059A (zh) 使用甲基巴多索隆或其类似物治疗covid-19的方法
Ban et al. Nicotinic Acid in the Treatment of Schizophrenias: Summary Statement Progress Report I Canadian Mental Health Association Collaborative Study
WO2021218965A1 (zh) 茜草科类型环肽化合物在制备cGAS-STING信号通路激活剂的药物中的应用
TWI776234B (zh) 藥學組合物及其於治療肌少症之用途
WO2012081713A1 (ja) 血液脳関門障害症候群治療薬
EP3991729A1 (en) Use of amlexanox in preparing anti-hepatitis virus drug
KR20230143978A (ko) 시클로-히스프로를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 약제학적 제제
MX2013001583A (es) Agente profilactico para esteatohepatitis no alcoholica.
WO2022245089A1 (ko) 타우로데옥시콜린산 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 코로나바이러스감염증-19(covid-19) 치료용 조성물
Lin et al. Metformin ameliorates neuronal necroptosis after intracerebral hemorrhage by activating AMPK
Literati-Nagy et al. Synergetic insulin sensitizing effect of rimonabant and BGP-15 in zucker-obes rats
US10071077B2 (en) Use of enoximone in the treatment of atopic immune-related disorders, in pharmaceutical composition as well as in pharmaceutical preparation
Liu et al. No effect of adjunctive minocycline treatment on body metabolism in patients with schizophrenia
CN111700889A (zh) 柚皮素在制备治疗癌症恶病质药物中的应用
JP2008239500A (ja) レプチン分泌促進剤
WO2004032924A1 (fr) Emploi de berberine en tant que sensibilisant insulinique
US20230270727A1 (en) Use of vegf inhibitor in preparation of medicament for treating hypoxia-related diseases
WO2024041633A1 (zh) 一种稠环嘧啶类化合物的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18920827

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18920827

Country of ref document: EP

Kind code of ref document: A1