CN116509854A - 一种萘啶酮衍生物的应用 - Google Patents
一种萘啶酮衍生物的应用 Download PDFInfo
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- VHSIAYLBCLUAFT-UHFFFAOYSA-N n-[3-acetyl-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-1-methyl-2-oxo-1,8-naphthyridin-4-yl]acetamide Chemical class C=1C=C(Cl)C=CC=1C=1C=C2C(NC(=O)C)=C(C(C)=O)C(=O)N(C)C2=NC=1C1=CC=C(Cl)C=C1Cl VHSIAYLBCLUAFT-UHFFFAOYSA-N 0.000 title claims description 29
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
本发明提供一种萘啶酮衍生物的应用，具体是该萘啶酮衍生物在制备防治非酒精性脂肪性肝纤维化的药物中的应用，该萘啶酮衍生物制备的药物能有效改善高脂饮食引起的肝脏纤维化程度，能够防治非酒精性脂肪性肝纤维化。
Description
技术领域：
本发明涉及一种萘啶酮衍生物的应用，即其在制备防治非酒精性脂肪性肝纤维化的药物中的应用。
背景技术：
非酒精性脂肪性肝病(Nonalcoholic Fatty Liver Disease，NAFLD)，又称代谢相关脂肪性肝病(Metabolic associated Fatty Liver Disease，MAFLD)，是指排除酒精和其他明确因素所致的以肝实质细胞脂肪变性和脂肪过渡沉积为主要特征的临床病理综合征(World J Gastroenterol,2014,20(27):9026-9037)。非干预状态下，病程可分为单纯性脂肪肝、非酒精性脂肪性肝炎、肝纤维化、肝硬化和肝细胞癌系列疾病谱。肝纤维化是该病发展为肝硬化的必经阶段，是该病主要预后指标和死亡率最重要的预测指标。肝纤维化病理特征表现为肝内弥漫性细胞外基质(Extracellular matrix，ECM)过度沉积。肝星状细胞(Hepatic stellate cells，HSC)活化被公认为肝纤维化发生的核心事件。活化的HSC大量增殖并转化为肌成纤维细胞，分泌过多胶原(ECM主要成分)沉积于肝脏细胞间隙，破坏肝脏结构，损害肝脏功能(Gut,2015,64(5):830-841)。因此抑制HSC的活化及胶原沉积在防治肝纤维化发生、发展过程中至关重要。
NAFLD已发展成为全球公共卫生问题，累及世界各国总人口24％，在肥胖人群中的发病率高达75％，已成为全球第一大肝病(Hepatol Res,2015,45(7):728-738)。由其发展而来的晚期肝纤维化和肝硬化已被证实为终末期肝功能衰竭的主要原因(Nat RevGastroenterol Hepatol,2019Mar；16(3):145-159)。据调查，我国成人患病率已达32.3％，该病已取代乙肝，成为我国第一大慢性肝病(Hepatol,2019,70(4):1119-1133)。但迄今为止，尚无公认的治疗NAFLD的有效药物。
发明内容：
本发明的目的是提供一种萘啶酮衍生物在制备防治非酒精性脂肪性肝病纤维化的药物中的应用。
本发明采用的技术方案是：
本发明提供一种式I所示萘啶酮衍生物或其药学上可接受的盐、立体异构体、溶剂合物在制备防治非酒精性脂肪性肝病纤维化的药物中的应用，尤其是通过抑制Acta2、Col1a1的表达防治非酒精性脂肪性肝病纤维化的药物。
进一步，所述式I所示萘啶酮衍生物在制备防治非酒精性脂肪性肝病纤维化的药物中的应用。
进一步，所述防治非酒精性脂肪性肝病纤维化的药物由所述式I所示萘啶酮衍生物或其药学上可接受的盐、立体异构体、溶剂合物与药学上可接受的载体组成。
所述药学上可接受的载体是指药学领域常规的药物载体，包括药学领域的常规稀释剂如水等，填充剂如淀粉等，粘合剂如纤维素衍生物、明胶等，湿润剂如甘油，崩解剂如琼脂、碳酸钙等，吸收促进剂如季铵化合物，表面活性剂如十六烷醇，吸附载体如高岭土、皂黏土，润滑剂如滑石粉等、增稠剂如羧甲基纤维素钠等。所述药学上可接受的载体为稀释剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的一种或两种以上。必要时还可以加入香味剂，甜味剂等。
药物制剂适用于通过任何适当途径给药，如口服(包括含服或舌下给药)、直肠给药、经鼻给药、局部给药(包括含服、舌下给药或经皮给药)或胃肠外给药(包括皮下注射、肌内注射、静脉注射或皮内注射)途径。这些制剂可由药剂学领域中已知的任何方法制备。例如通过将活性成分与载体或赋形剂混在一起的方法。
在本发明的一个实施例中，所述防治非酒精性脂肪性肝病纤维化的药物由式I所示萘啶酮衍生物与5mg/mL羧甲基纤维素钠的水溶液组成。
在本发明的一个实施例中，给药剂量以活性物质的质量计为30mg/kg(体重)。
与现有技术相比，本发明的有益效果主要体现在：
本发明中，从NALFD小鼠造模第9周起，以30mg/kg/d浓度式I所示萘啶酮衍生物干预16周，相比疾病组小鼠，干预组小鼠肝组织胶原沉积明显减少；HSC活化标志性基因Acta2核酸及蛋白表达水平显著降低；胶原Col1a1核酸及蛋白表达显著降低。因此，式I所示萘啶酮衍生物可以有效改善NAFLD小鼠肝组织纤维化。因此，式I所示萘啶酮衍生物能有效降低高脂饮食引起的肝脏纤维化程度，能够防治非酒精性脂肪性肝纤维化。
附图说明：
图1为各组小鼠马松(Masson)染色病理。(标尺代表100μm)。
图2为式I所示萘啶酮衍生物对小鼠肝脏Acta2核酸表达的影响。(柱状图中，不同字符的条形图之间有显著性差异，P<0.05)。
图3为式I所示萘啶酮衍生物对小鼠肝脏Col1a1核酸表达的影响。(柱状图中，不同字符的条形图之间有显著性差异，P<0.05)。
图4为式I所示萘啶酮衍生物对小鼠肝脏Acta2蛋白表达的影响。图A为Westernblot检测蛋白表达结果，图B为相对积分灰度统计结果(柱状图中，不同字符的条形图之间有显著性差异，P<0.05)。
图5为式I所示萘啶酮衍生物对小鼠肝脏Col1a1蛋白表达的影响。图A为免疫组化检测蛋白表达结果，图B为相对积分灰度统计结果(标尺表示100μm；柱状图中，不同字符的条形图之间有显著性差异，P<0.05)。
具体实施方式：
以下附图和实施例对本发明做进一步详细描述，但本发明的保护内容并不仅限于此。
1.材料：
1.1实验动物：
C57BL/6J品系SPF级，6～8周龄雄性小鼠，购自浙江维通利华实验动物技术有限公司，生产许可证编号：SCXK(浙)2019-0001，饲养于浙江中医药大学动物实验研究中心。
1.2饲料：
正常饲料由浙江中医药大学动物实验研究中心提供，高脂饲料购自南通特洛菲饲料科技有限公司。普通饲料供能比为：21.6％蛋白质、12.3％脂肪、66.1％碳水化合物；高脂饲料喂养供能比：21.6％蛋白质、36.1％脂肪、42.3％碳水化合物。
1.3试剂：
CMC-Na购自Selleckchem公司，货号为S6803。式I所示萘啶酮衍生物购自APExBIO公司，货号为B2301。
1.4qRT-PCR相关试剂及引物：
RNA提取试剂盒TaKaRaMiniBEST Universal RNAExtraction Kit购自TaKara公司，货号9767。反转录试剂预混液Evo M-MLV RT Premix for qPCR购自湖南艾科瑞生物工程有限公司，货号：AG11706。SYBR Green Pro Taq HS预混型qPCR试剂盒GreenPremix Pro Taq HS qPCR Kit购自湖南艾科瑞生物工程有限公司，货号：AG11701。仪器为CFX-384Bio-Rad。
引物信息如下：
| 基因名称 | 引物序列(正向) | 引物序列(反向) |
| Acta2 | GTCCCAGACATCAGGGAGTAA | TCGGATACTTCAGCGTCAGGA |
| Col1a1 | GCTCCTCTTAGGGGCCACT | CCACGTCTCACCATTGGGG |
| β-Actin | AGAGGGAAATCGTGCGTGAC | CAATAGTGATGACCTGGCCGT |
1.5Western blot及免疫组化抗体：
Acta2抗体购自Abcam公司，货号ab32575。Col1a1抗体购自Cell SignalingTechnology公司，货号72026S。Gapdh抗体购自联科生物技术有限公司，货号Mab5465-100。Goat anti-Rabbit IgG购自联科生物技术有限公司，货号GAR0072。
2.实验方法：
2.1疾病模型构建：小鼠适应性饲养1周后，随机分为3组：即正常组(6只)、疾病组(6只)、式I萘啶酮衍生物干预组(6只)。正常组以普通饲料喂养，其他两组以高脂饲料喂养，共24周。
2.2实验给药：从高脂饮食第9周起，式I萘啶酮衍生物组以每天30mg/kg(小鼠体重)式I萘啶酮衍生物(以5mg/mL CMC-Na的水溶液溶解)灌胃，正常组和疾病组小鼠每天灌服等容量溶剂5mg/mL CMC-Na(羧甲基纤维素钠)的水溶液，至24周末。
2.3标本采集：24周末处理全部小鼠，各组小鼠处理前一晚禁食不禁水12小时，麻醉下取血，并收集肝脏标本，部分放入固定液中固定之后进行石蜡包埋用于病理观察及免疫组化，剩余肝脏组织用于分子检测。
3.检测指标：
3.1肝脏组织病理学实验
马松(Masson)染色：小鼠肝组织石蜡切片经脱蜡和水化后，进行染色，用来显示组织中胶原沉积情况。镜检观察染色情况，用数字病理切片扫描仪(AxioScan.Z1)进行扫描。具体实验方法为现有技术在此不详细描述。结果见图1。
3.2肝脏纤维化指标检测
提取小鼠肝组织RNA，用qRT-PCR法检测肝组织中Acta2、Col1a1基因核酸表达情况，具体实验方法为现有技术在此不详细描述。分析结果，结果见图2、3。
提取小鼠肝组织蛋白，用Western blot法检测肝组织中Acta2蛋白表达情况。具体实验方法为现有技术在此不详细描述，分析结果见图4。
用免疫组化法检测小鼠肝组织Col1a1蛋白表达情况，镜检观察染色情况，用数字病理切片扫描仪(AxioScan.Z1)进行扫描。具体实验方法为现有技术在此不详细描述，分析结果，结果见图5。
3.3统计学方法
采用SPSS22.0软件包进行数据统计分析。所有计量资料均以均数±标准差(Mean±SD)表示。采用单因素方差分析，各组之间两两比较。若方差齐性时采用LSD检验，若方差不齐时采用Dunnett’s T3检验。以P<0.05为差异有统计学意义。
4.实验结果：
图1为本发明式I萘啶酮衍生物对小鼠肝组织胶原沉积的影响。马松(Masson)染色结果显示，正常组小鼠肝组织结构正常，细胞间质仅有少量蓝色胶原沉积；疾病组小鼠肝组织结构破坏严重，细胞间质出现大量蓝色胶原沉积；式I萘啶酮衍生物干预组小鼠肝脏胶原沉积明显减少。
图2为本发明式I萘啶酮衍生物对小鼠肝组织中Acta2基因mRNA表达水平的影响。结果显示，对比正常组，疾病组Acta2表达量显著升高；对比疾病组，式I萘啶酮衍生物干预组Acta2表达量显著下降。
图3为本发明式I萘啶酮衍生物对小鼠肝组织中Col1a1基因mRNA表达的影响。结果显示，对比正常组，疾病组Col1a1表达量显著升高；对比疾病组，式I萘啶酮衍生物干预组Col1a1表达量显著下降。
图4为本发明式I萘啶酮衍生物对小鼠肝组织中Acta2蛋白表达水平的影响。结果显示，对比正常组，疾病组Acta2蛋白表达量显著升高；对比疾病组，式I萘啶酮衍生物干预组Acta2蛋白表达量显著下降。图A为各组Western blot检测情况，图B为积分灰度值统计相对表达量结果。
图5为本发明式I萘啶酮衍生物对小鼠肝组织中Col1a1蛋白表达水平的影响。结果显示，对比正常组，疾病组小鼠肝组织胞外基质中Col1a1胶原沉积显著升高；对比疾病组，式I萘啶酮衍生物干预组织胞外基质中Col1a1胶原沉积显著下降。图A为各组免疫组化检测情况，图B为积分灰度值统计相对表达量结果。
Claims (10)
1.一种式I所示萘啶酮衍生物或其药学上可接受的盐、立体异构体、溶剂合物在制备防治非酒精性脂肪性肝病纤维化的药物中的应用，
2.如权利要求1所述式I所示萘啶酮衍生物在制备防治非酒精性脂肪性肝病纤维化的药物中的应用。
3.如权利要求1所述的应用，其特征在于：所述防治非酒精性脂肪性肝病纤维化的药物由所述的式I所示萘啶酮衍生物或其药学上可接受的盐、立体异构体、溶剂合物与药学上可接受的载体组成。
4.如权利要求1或2所述的应用，其特征在于：所述药学上可接受的载体为稀释剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的一种或两种以上。
5.如权利要求4所述的应用，其特征在于：所述稀释剂为水。
6.如权利要求4所述的应用，其特征在于：所述填充剂为淀粉，所述粘合剂为纤维素衍生物或明胶。
7.如权利要求4所述的应用，其特征在于：所述湿润剂为甘油，所述崩解剂为琼脂或碳酸钙，所述吸收促进剂为季铵化合物，所述表面活性剂为十六烷醇，所述吸附载体为高岭土或皂黏土。
8.如权利要求4所述的应用，其特征在于：所述润滑剂为滑石粉。
9.如权利要求4所述的应用，其特征在于：所述增稠剂为羧甲基纤维素钠。
10.如权利要求1或2所述的应用，其特征在于：所述防治非酒精性脂肪性肝病纤维化的药物由式I所示萘啶酮衍生物与5mg/mL羧甲基纤维素钠的水溶液组成。
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