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WO2019024758A1 - 一种糖苷类化合物在制备用于治疗肝纤维化药物中的应用 - Google Patents

一种糖苷类化合物在制备用于治疗肝纤维化药物中的应用 Download PDF

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WO2019024758A1
WO2019024758A1 PCT/CN2018/097201 CN2018097201W WO2019024758A1 WO 2019024758 A1 WO2019024758 A1 WO 2019024758A1 CN 2018097201 W CN2018097201 W CN 2018097201W WO 2019024758 A1 WO2019024758 A1 WO 2019024758A1
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liver
fibrosis
hepatic fibrosis
liver fibrosis
compound
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PCT/CN2018/097201
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张勇慧
向明
刘婷婷
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华中科技大学
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Priority to US16/779,686 priority Critical patent/US11154567B2/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

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  • the invention belongs to the technical field of medicine and relates to a medicine for treating liver diseases, in particular to a medicine for treating liver fibrosis, that is, a medicament for preparing a medicine for treating liver fibrosis.
  • Fibrosis of liver is a pathological change caused by chronic liver damage caused by various causes. It is characterized by excessive and abnormal deposition of extracellular interstitial components in the liver and affects liver function. It is the development of chronic liver disease to cirrhosis. In the necessary stage, liver fibrosis is a precancerous lesion of cirrhosis, so it is of clinical significance (References: Xia Haishan, Chen Shaoru, Zhong Yuechun, et al. Pathogenesis of liver fibrosis and current status of drug treatment [J]. China Medical Herald).
  • liver fibrosis is a necessary way for various liver diseases such as hepatitis B, hepatitis C, and fatty liver to develop into cirrhosis, so preventing the development of liver fibrosis is to save tens of millions
  • the life of patients with liver disease is of great significance.
  • Current clinical research on liver fibrosis focuses on molecular and molecular, molecular and cellular, and cell-to-cell interactions. Although there have been some progress in the diagnosis and treatment, there is still a lack of effective drugs.
  • the existing drugs such as silymarin can only delay the development of the disease, and have no obvious effect on reversing the disease.
  • liver fibrosis Most of the pathological changes of human liver fibrosis develop slowly, from liver cell damage, inflammation, necrosis, abnormal proliferation and deposition of extracellular matrix, and some need to go through several months to several years, with an average of about 3 to 5 years. time. Because the liver has a strong compensatory function, even if liver fibrosis is active, the patient's clinical performance is not typical; even if the patient has symptoms, it often lacks characteristics. Many patients were examined by physical examination or laparotomy for other diseases, even when they were autopsied (Zeng Zhiping, Guo Jinsheng. Progress in the mechanism and treatment of liver fibrosis [J]. World Chinese Journal of Digestion). Therefore, exploring and developing an effective drug for the treatment of liver fibrosis is an important topic in the field for a long time.
  • Natural products are the most common source of drugs. According to statistics, from the 1980s to the present, 30-40% of listed drugs are directly or indirectly derived from natural products. In 2010, the proportion of drugs related to natural products was as high as 50. %. The types of secondary metabolites in plants are extremely rich. With the increasing research in recent years, more and more active compounds have been discovered, which laid a foundation for the development of new drugs. The present invention aims to find an effective drug for treating liver fibrosis from natural products.
  • the present invention provides a drug for treating liver fibrosis, which is Kinsenoside (3-(R)-3- ⁇ -D-Glucopyranosyloxybutanolide).
  • Astragalus sinensis is a special component of the genus Orchidaceae, and the content of three common species of the genus Largo, such as the genus Lilium sinensis, Hengchun, and the golden orchid, are 16% and 15%, respectively. 16% (dry weight) (Wang Jiandong, Wang Hongzhen, Zhang Ailian, Shao Qingsong. Research progress of adiponectin [J]. Chinese Journal of Hospital Pharmacy). The literature has a wide range of pharmacological activities, including blood sugar lowering, diabetes treatment, blood fat reduction and weight loss, liver protection and liver protection, protection against endothelial cells, improvement of osteoporosis, inhibition of inflammatory response, etc.
  • Liver coefficient liver mass/body mass
  • spleen coefficient spleen mass/body mass
  • histopathological analysis showed that the liver surface of the mice treated with amlidine was smooth, the color was reddish brown, and the hepatocytes were swollen.
  • the degree of necrosis and inflammatory cell infiltration was significantly lighter than that of the model control group (Reference: Hu Guanghua. The activity of heparin and the synthesis of peracetyl compounds [M]. Huazhong University of Science and Technology). At present, there is only a research report on the application of adiponectin.
  • This compound has not been officially marketed, and it is a classic liver for the injection of AKT (Serine/threonine Kinase) and transposase plasmids by hydrodynamics combined with transposition system.
  • AKT Serine/threonine Kinase
  • transposase plasmids hydrodynamics combined with transposition system.
  • the research on fibrosis model modeling has not been carried out yet.
  • the inventors have explored the therapeutic effect of the fibrosis model induced by the injection of AKT and transposase in the therapeutic fluid mechanics combined with the transposition system. More significant results.
  • Astragalus is a glycosidic compound, and the structural formula of aurantium is shown in Formula 1:
  • the adiponectin used in the study of the present invention was purchased from Shanghai Tongtian Biotechnology Co., Ltd., and the purity was >98.0%.
  • the present inventors evaluated the activity of liver fibrosis by treating the compound fibroin, and found that the compound can effectively prevent the development of liver fibrosis, and produce a certain reduction of fibrosis marker gene expression, liver function and oxidative stress in vivo. Damage, reducing the secretion of inflammatory factors and other activities, can be used as a lead compound in the development of drugs for the treatment of liver fibrosis.
  • Figure 1 The therapeutic role of KD in NAFL-NASH, the overall course of liver fibrosis,
  • FIG. 3 KD inhibits HSC-T6 from exerting liver protection.
  • HSC-T6 (A) cell cycle; (B) proliferation; (C) apoptosis; (D) activation, ECM secretion-related gene mRNA and protein expression.
  • Example 1 The treatment of liver fibrosis by kinsenoside (KD).
  • Astragalus sinensis was purchased from Shanghai Tongtian Biotechnology Co., Ltd. with a purity of >98.0%.
  • Hematoxylin-eosin (H&E) staining showed that KD can alleviate liver tissue disease in high dose group (30mg/kg KD), middle dose group (20mg/kg KD) and low dose group (10mg/kg KD). Physical damage; Masson staining showed that KD inhibited fiber formation (see Figure 1A).
  • Real-time shear wave elastography (SWE) ultrasound was used to detect the development of liver fibrosis in mice and the therapeutic potential of KD.
  • liver disease was in mild and moderate stages, and the hepatic portal vein and inferior vena cava, liver left lobe thick diameter, right hepatic lobe diameter, spleen length and thickness did not change significantly; when chronic hepatitis developed to the liver In the stage of fibrosis and cirrhosis, the inferior vena cava was significantly widened, the thickness of the left lobe of the liver increased significantly, the spleen increased significantly, and the hepatic portal vein, right lobe slant diameter and spleen length also increased.
  • KD treatment significantly reduced the inferior vena cava width, left hepatic lobe thickness, right hepatic lobe diameter, and spleen thickness in the high-dose, middle-dose, and low-dose groups (see Table 1).
  • the shear wave velocity measurement of SWE showed that the echo velocity of the left and right lobe of the model group was significantly increased, suggesting that the liver tissue was hard and fibrotic lesions were severe, while KD significantly reduced the shear wave velocity and relieved liver fibrosis ( See Figure 1B).
  • qPCR was used to detect the expression of fibrosis marker gene in liver tissue.
  • the results also showed that KD can effectively inhibit ⁇ -smooth muscle actin ( ⁇ -SMA) in high-dose, middle-dose and low-dose mice.
  • ⁇ -SMA smooth muscle actin
  • liver function tests showed that serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the model group were higher than those in the control group, and decreased after KD treatment; lipid peroxidation products in the model group Malondialdehyde MDA expression increased and superoxide dismutase (SOD) activity decreased, and treatment with KD reversed these oxidative stress lesions (see Figure 2).
  • ALT serum alanine aminotransferase
  • AST aspartate aminotransferase
  • HSCs The activation of HSCs is the central link in the development of liver fibrosis, and its apoptosis can reverse liver fibrosis.
  • the experiment used different concentrations of KD to act on TGF- ⁇ 1 activated rat hepatic stellate cells (HSC-T6).
  • HSC-T6 TGF- ⁇ 1 activated rat hepatic stellate cells
  • the results showed that the action of KD blocked the cell cycle of HSC-T6 in the G0/G1 phase, inhibited its proliferation, and promoted apoptosis (see Figure 3A-C).
  • qPCR and Western blot experiments also showed that HSC-T6 cell activation and ECM secretion related genes and protein expression were also inhibited by KD (see Figure 3D).
  • the results are shown in Figures 1-3 and Table 1-3.
  • Astragalus has a good therapeutic effect on liver fibrosis, which can effectively prevent the development of liver fibrosis and improve liver damage.
  • the mechanism is that the compound can reduce the expression of fibrosis marker gene, improve liver function and oxidation. Injury, reduce the secretion of inflammatory factors and other activities.

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Abstract

本发明属于医药技术领域，提供了一种治疗肝纤维化的药物，本发明通过对化合物金线莲苷的治疗肝纤维化活性进行评价，发现该化合物能够有效阻止肝纤维化的发展，在体内产生一定的降低纤维化标志基因表达、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性，可以作为治疗肝纤维化药物开发的先导化合物。

Description

一种糖苷类化合物在制备用于治疗肝纤维化药物中的应用 技术领域
本发明属于医药技术领域，涉及治疗肝脏疾病的药物，具体涉及治疗肝纤维化的药物，即一种糖苷类化合物在制备用于治疗肝纤维化药物中的应用。
背景技术
肝纤维化(fibrosis of liver)是多种原因引起的慢性肝损害所致的病理改变，表现为肝内细胞外间质成分过度异常地沉积，并影响肝脏的功能，是慢性肝病发展到肝硬化必经之阶段，肝纤维化是肝硬化的前期病变，因此在临床上具有重要意义(参考文献：夏海珊，陈少茹，钟月春，等.肝纤维化的发病机制和药物治疗现况[J].中国医药导报)。关于肝纤维化的发病率和患病率的可靠数据不易统计，因为它没有明显的症状，更重要的是没有准确的非侵入性诊断方法，但可以从以下数据中窥见一斑：全球肝硬化的患病人数超过6000万，在肝硬化的变化过程中患者均经历了数年甚至数十年的肝纤维化过程(参考文献：范慧宁，陈尼维.肝纤维化的流行病学研究进展[J].国际消化病杂志)，且肝纤维化是乙型肝炎、丙型肝炎、脂肪肝等多种肝脏疾病发展至肝硬化的必经途径，故阻止肝纤维化的发展对于挽救数以千万计肝脏疾病患者的生命具有重要意义。目前临床对于肝纤维化的研究重点放在分子与分子、分子与细胞及细胞与细胞间的相互作用方面。在诊治方面虽然有一些进展，但仍缺乏确定有效的药物，现有的水飞蓟素等药物仅能够延缓疾病的发展，对于逆转疾病则无明显效果。人类肝纤维化的病理改变多数发展较为缓慢，从肝细胞的损伤、炎症、坏死、细胞外基质的异常增生和沉积，有的需要经过数月至数年之久，平均约3～5年的时间。由于肝脏具有很强的代偿功能，即使肝纤维化处于活动期，病人的临床表现也不典型；即使病人有症状，往往也缺乏特征性。许多患者是在体格检查或因其他疾病进行剖腹探查，甚至在尸体解剖时才被发现(曾志萍,郭津生.肝纤维化发生机制及治疗研究进展[J].世界华人消化杂志)。因此，探索研究开发一种治疗肝纤维化的有效药物，是该领域长期以来的重要课题。
天然产物是药物最常见的来源，据统计，从上世纪八十年代年至今，每年30-40％的 上市药物直接或间接来源于天然产物，其中2010年，天然产物相关来源的药物比例高达50％。植物次生代谢产物的种类极为丰富，随着近年对其研究的不断增多，越来越多活性强的化合物被发现，为新药的研发奠定了一定的基础。本发明旨在从天然产物中寻找治疗肝纤维化的有效药物。
发明内容
本发明的任务是提供一种治疗肝纤维化药物。
实现本发明的技术方案是：本发明提供治疗肝纤维化药物是金线莲苷(Kinsenoside(3-(R)-3-β-D-Glucopyranosyloxybutanolide))。
金线莲苷为兰科开唇兰属植物特质性成分，花叶开唇兰、恒春金线莲和金线兰等3种常见的开唇兰植物中含量分别为16％、15％及16％(干重)(王建栋，王红珍，张爱莲，邵清松.金线莲苷研究进展[J].中国医院药学杂志)。文献金线莲苷具有较为广泛的药理活性，包括降血糖、治疗糖尿病作用、降血脂和减肥作用、保肝护肝作用、对内皮细胞的保护作用、改善骨质疏松作用、抑制炎症反应等(参考文献：何春年，王春兰，郭顺星，等.兰科开唇兰属植物的化学成分和药理活性的研究[J].中国药学杂志)。对于金线莲苷的保肝护肝活性研究，目前主要集中在四氯化碳诱导的小鼠急、慢性肝损伤模型，研究结果显示，该化合物可有效改善小鼠谷丙转氨酶、谷草转氨酶、肝脏系数(肝脏质量/体质量)及脾脏系数(脾脏质量/体质量)，而组织病理学分析表明，金线莲苷给药组小鼠肝脏表面比较光滑，颜色为红褐色，肝细胞肿胀、坏死和炎症细胞浸润程度明显轻于模型对照组(参考文献：胡光华.金线莲苷保肝降酶活性及其全乙酰化合物的合成[M].华中科技大学)。目前，对于金线莲苷的应用仅见研究性报道，该化合物尚无正式药物上市，针对采用流体力学法联合转座系统注射AKT(Serine/threonine Kinase)及转座酶的质粒这种经典的肝纤维化模型造模研究更是尚未开展，发明人针对这一问题，对治疗流体力学法联合转座系统注射AKT及转座酶的质粒所致纤维化模型的治疗作用进行了探讨，并取得了较显著的成果。
金线莲苷属于糖苷类化合物，金线莲苷的结构式如式1所示：
Figure PCTCN2018097201-appb-000001
本发明研究使用的金线莲苷购买自上海同田生物技术股份有限公司，纯度>98.0％。
本发明人通过对化合物金线莲苷的治疗肝纤维化活性进行评价，发现该化合物能够有效阻止肝纤维化的发展，在体内产生一定的降低纤维化标志基因表达、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性，可以作为治疗肝纤维化药物开发的先导化合物。
附图说明
图1：KD在NAFL——NASH——肝纤维化整体病程中的治疗作用，
(A)肝组织病理损伤；
(B)超声检测肝脏、脾脏病变情况；
(C)肝纤维化标志基因表达情况。
图2：KD对肝纤维化小鼠肝功能和氧化应激的影响，
(A)肝功能；
(B)氧化应激。
图3：KD抑制HSC-T6发挥保肝作用。HSC-T6(A)细胞周期；(B)增殖；(C)凋亡；(D)活化、ECM分泌相关基因mRNA及蛋白表达。
具体实施方式
实施例1：金线莲苷(kinsenoside；KD)治疗肝纤维化作用。
金线莲苷购买自上海同田生物技术股份有限公司，纯度>98.0％。
本实验取6-8周龄的FVB/N小鼠，分为空白组(control group)、模型组(model group)、高剂量组(30mg/kg KD)、中剂量组(20mg/kg KD)和低剂量组(10mg/kg KD)。采用 流体力学法联合转座系统注射AKT及转座酶的质粒，特异性在肝内过表达AKT，对除空白组外的小鼠进行造模。造模1周后即形成单纯性脂肪肝(NAFL)，2周后形成脂肪性肝炎(NASH)，4周即能在肝脏造成原发性肝纤维化模型。在NAFL——NASH——肝纤维化整体病程中，观察KD的治疗作用。苏木精-伊红(H&E)染色结果显示，高剂量组(30mg/kg KD)、中剂量组(20mg/kg KD)和低剂量组(10mg/kg KD)中，KD可减轻肝脏组织病理学损伤；Masson染色结果显示，KD对纤维形成有抑制作用(见图1A)。采用实时剪切波弹性成像(SWE)超声技术检测小鼠肝纤维化发展情况以及KD的治疗潜能。结果显示，NASH期，肝病处于轻度和中度阶段，小鼠肝门静脉和下腔静脉，肝左叶厚径，肝右叶斜径及脾脏长度、厚度变化不明显；当慢性肝炎发展到肝纤维化、肝硬化阶段时，下腔静脉明显加宽，肝左叶厚径显著增长，脾脏明显增厚，肝门静脉、肝右叶斜径和脾长也有增宽增长趋势。KD的治疗能显著缩小高剂量组、中剂量组和低剂量组小鼠下腔静脉宽度、肝左叶厚径、肝右叶斜径及脾脏厚度(见表1)。SWE的剪切波速度测量结果显示，模型组小鼠左右叶肝脏的回声速度显著增大，提示肝组织硬度大，纤维化病变严重，而KD可显著降低剪切波速度，缓解肝纤维化(见图1B)。qPCR检测肝组织中纤维化标志基因表达情况，结果也显示，KD可有效抑制高剂量组、中剂量组和低剂量组小鼠肝脏α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、一型胶原(collagen-I,Col I)、基质金属蛋白酶抑制剂-1(tissue inhibitor of metalloproteinase-1,TIMP-1)的表达，上调基质金属蛋白酶-13(matrix metalloproteinase-13,MMP-13)的表达(见图1C)。
在肝纤维化病程发展过程中，肝功能检查结果提示，模型组血清谷丙转氨酶(ALT)，谷草转氨酶(AST)水平较对照组上升，给予KD治疗后下降；模型组脂质过氧化反应产物丙二醛MDA表达上升，超氧化物歧化酶(SOD)活性下降，给予KD治疗可以逆转这些氧化应激损伤(见图2)。
在肝纤维化病程发展过程中，KD的治疗降低了高剂量组、中剂量组和低剂量组小鼠促炎Th1型细胞分泌的炎症因子——IFN-γ、TNF-α和IL-2的分泌；升高抗炎Th2型细胞因子——IL-10的分泌，抑制炎症应答标志NO的释放(见表2,3)。KD的治疗作用呈现出一定剂量依赖性，作用效果与阳性药水飞蓟素相当，在某些指标中效果优于阳性 药。与此同时，阴性对照组给予健康小鼠KD，不影响其ALT，AST和炎性因子分泌。HSCs是参与肝纤维化的重要细胞，HSCs的活化是肝纤维化发生发展的中心环节，而其凋亡可以逆转肝纤维化。实验使用不同浓度的KD作用于TGF-β 1激活的大鼠肝星状细胞(HSC-T6)。结果显示，KD的作用可使HSC-T6细胞周期阻滞于G0/G1期，抑制其增殖，并可促进其凋亡(见图3A-C)。qPCR和Western blot实验也显示，HSC-T6细胞激活和ECM分泌的相关基因、蛋白表达也被KD的作用抑制(见图3D)。结果如图1-3及表1-3所示。
表1.B超检测小鼠肝脏、脾脏组织病理损伤
Table 1 Type B ultrasonic detector of the liver and spleen(means±SD,n＝3).
Figure PCTCN2018097201-appb-000002
**P＜0.01 compared with control group； #P＜0.05， ##P＜0.01 compared with model group.
表2.KD对NASH小鼠血清炎症因子分泌的影响
Table 2 Effect of KD on the secretion of inflammatory cytokines in NASH(means±SD，n＝6).
Figure PCTCN2018097201-appb-000003
表3.KD对肝纤维化小鼠血清炎症因子分泌的影响
Table 3 Effect of KD on the secretion of inflammatory cytokines in liver fibrosis(means±SD,n＝6).
Figure PCTCN2018097201-appb-000004
**P＜0.01 compared with control group； #P＜0.05, ##P＜0.01 compared with model group；
ΔP＜0.05， ΔΔP＜0.01 compared with silymarin group.
实验结论：金线莲苷对肝纤维化具有较好的治疗作用，能够有效阻止肝纤维化的发展，改善肝脏损伤，其机制在于该化合物可降低纤维化标志基因表达、改善肝功能和氧化应激损伤、降低炎性因子分泌等活性。

Claims (2)

  1. 金线莲苷(Kinsenoside(3-(R)-3-β-D-Glucopyranosyloxybutanolide)在制备用于治疗肝纤维化药物中的应用。
  2. 权利要求1中所述的金线莲苷具有以下式1所示结构
    Figure PCTCN2018097201-appb-100001
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