CN114788826A - Magl抑制剂在制备防治肝纤维化药物中的应用 - Google Patents
Magl抑制剂在制备防治肝纤维化药物中的应用 Download PDFInfo
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- CN114788826A CN114788826A CN202111572610.5A CN202111572610A CN114788826A CN 114788826 A CN114788826 A CN 114788826A CN 202111572610 A CN202111572610 A CN 202111572610A CN 114788826 A CN114788826 A CN 114788826A
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明属于医药领域。本发明的目的是提供MAGLⅡ‑11在制备防治肝纤维化药物中的用途。本发明的MAGLⅡ‑11对于免疫性肝纤维化和/或化学性肝纤维化具有显著的治疗效果。MAGLⅡ‑11具有显著的抗肝纤维化效果，能够提高存活率，降低血清TP、ALB、ALT、AST、HA、pcIII含量，降低肝脏Hyp含量，改善肝纤维化病理变化。
Description
技术领域
本发明属于医药领域，涉及一种抗肝纤维化的化合物及其用途，具体涉及式Ⅰ所述的化合物及其在制备预防或治疗肝纤维化药物中的医药用途。
背景技术
肝纤维化是指肝脏内弥漫性细胞外基质(特别是胶原物质)过度沉积，是机体对各种病因引起的慢性肝损伤后的一种损伤修复反应，表现为肝内胶原纤维异常增生，肝细胞变性坏死，肝组织结构和功能遭到破坏，造成肝功能异常，影响肝病预后。肝纤维化如不及时治疗则可能进展成为失代偿期肝硬化并出现各种终末期肝病并发症，肝硬化及其并发症已经成了全球发病与死亡的主要因素，肝纤维化是很多肝病终末期阶段复杂病症发生的基础，如肝门静脉高压、肝腹水、合成功能紊乱、代谢能力受损等等。
近年来，国内外学者针对胶原代谢的诸个环节，提出了一系列抗肝纤维化的药物和疗法。①抑制胶原合成：a、肾上腺皮质激素。b、干扰素。c、前列腺素类似物。d、类固醇类物质。e、前胶原肽。②作用于前胶原的mRNA转译后：a、秋水仙碱。b、金属离子结合剂。c、脯氨酸-4-羟化酶抑制剂。d、脯氨酸类似物。e、前胶原向胶原后转化的抑制剂。f、山黎豆等。③促进胶原降解的治疗。以上药物和疗法有的因毒副作用较大或尚处于实验阶段，其确切疗效尚待进一步观察和探讨。西药联苯双酯有快速、显著的降酶作用，但停药后“反跳”(即肝功能异常指标加倍升高)，而且药物对肝脏病理组织的恢复也难说有确切效果。对病毒抑制方面，比较公认有效的药物是干扰素及其诱导剂阿糖腺苷等，但价格昂贵、副作用大，且对人体的神经系统、消化系统、心血管系统、泌尿系统及造血系统等均可造成不同程度的损害，还有过敏反应。
现代医学尚无安全、高效、廉价的抗肝纤维化药物问世，临床用药有干扰素、单味中药及中药复方等。这些药物有的价格昂贵，有的长期服用有毒副作用，有的效果不显著，重现性差，有的成分复杂，不利于深入研究药物的作用机制。因此，研发安全有效的治疗肝纤维化药物已成为当前药物研究的热点领域之一。
发明内容
本发明的目的在于提供MAGL抑制剂在制备抗肝纤维化药物中的应用，其对于肝纤维化具有显著的治疗效果，改善肝纤维化病理变化。
为实现上述发明目的，提供如下技术方案：
MAGLⅡ-11结构式如下：
本发明的目的是提供MAGLⅡ-11在制备防治肝纤维化药物中的用途。
本发明的MAGLⅡ-11对于免疫性肝纤维化和/或化学性肝纤维化具有显著的治疗效果。
MAGLⅡ-11具有显著的抗肝纤维化效果，能够提高存活率，降低血清TP、ALB、ALT、AST、HA、pcIII含量，降低肝脏Hyp含量，改善肝纤维化病理变化。
本发明实施例1研究了MAGLⅡ-11对CCl4所致大鼠肝纤维化的影响，发现MAGLⅡ-11提高肝纤维化模型的存活率，降低大鼠血清HA、pcIII含量，改善模型的肝纤维化病理变化。
本发明实施例2研究了MAGLⅡ-11对大鼠免疫性肝纤维化的影响，发现MAGLⅡ-11显著降低大鼠血清TP、ALB、ALT、AST，降低大鼠肝脏Hyp含量，具有显著的抗肝纤维化效果。
本发明提供MAGLⅡ-11在制备治疗和/或预防肝纤维化患病机体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产品中的应用。
本发明提供MAGLⅡ-11在制备治疗和/或预防肝纤维化患病机体肝脏Hyp增加的产品中的应用。
本发明提供MAGLⅡ-11在制备改善肝纤维化患病机体肝纤维化病理变化的产品中的应用。
本发明的MAGLⅡ-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。
所述用于预防和/或治疗酒精性脂肪肝的MAGLⅡ-11的给药方式可以为口服、滴注或注射。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
将本发明的MAGLⅡ-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。
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。
本发明的有益效果在于：
本发明公开了MAGLⅡ-11的抗肝纤维化活性，其能够提高存活率，降低血清TP、ALB、ALT、AST、HA、pcIII含量，降低肝脏Hyp含量，改善肝纤维化病理变化，对于肝纤维化具有显著的治疗效果，应用前景好。
具体实施方式
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。
实施例1 MAGLⅡ-11对CCl4所致大鼠肝纤维化作用研究
1.动物及实验分组
选用180-220g健康Wistar大鼠，76只，雌雄各半。
随机分成正常对照组、CCl4模型组、MAGLⅡ-11低剂量组、MAGLⅡ-11高剂量组及秋水仙碱组。
2.模型的建立
除正常对照组外，各组大鼠进行造模。方法如下：大鼠肝纤维化模型选用CCl4为诱导剂，CCl4小剂量长期注射(3个月)可造成肝纤维化模型。除正常对照组外，其余动物均饲以单纯玉米面(前两周加20％猪油)加胆固醇0.5％、食盐1％、饮自来水。实验第1天背部皮下注射CCl4原液5ml/kg体重，以后每隔3天皮下注射40％CCl4-橄榄油3ml/kg体重，6周后将40％CCl4-橄榄油的用量降为1.5mg/kg体重，同时给动物恢复正常的营养饲料。
造模周期缩短为6周。
分别于实验的3周末、6周末和8周处死动物。取血离心，收集血清，定位取肝组织进行肝纤维化指标的测定及病理组织学检查。
3.对大鼠肝纤维化的治疗作用
用加速法成功造模31天后，将64只肝纤维化大鼠随机分成CCl4模型组，MAGLⅡ-11低剂量组，MAGLⅡ-11高剂量组，秋水仙碱组，每组16只，雌雄各半。各组灌胃给药。剂量如下：
MAGLⅡ-11低剂量组：5mg/kg MAGLⅡ-11。
MAGLⅡ-11高剂量组：10mg/kg MAGLⅡ-11。
秋水仙碱组：0.1mg/kg秋水仙碱。
正常对照组、模型组给予等体积0.5％羧甲基纤维素钠。
开始进行治疗给药，每日一次，连续一个月。继续给予CCl4刺激，6周后将40％CCl4-橄榄油的注射剂量下调为1.5ml/kg体重，同时恢复正常营养饲料。实验结束时(8周)大鼠腹腔注射1％戊巴比妥钠麻醉，断颈取全血，离心收集血清，测定HA，PCⅢ含量。
4.检测项目及指标
用Elisa试剂盒检测血清HA、PCⅢ水平。
摘取肝脏左叶放入10％中性甲醛中固定，常规取材、脱水，HE染色，显微镜下观察肝脏纤维化程度，根据纤维结缔组织的纤维化程度将其分为0～4级。
0级:无纤维化；1级:纤维结缔组织仅局限于汇管区或汇管区有扩大，有向小叶发展的倾向；2级:纤维结缔组织增生明显，超过小叶的2/3并伴有1级改变；3级:纤维结缔组织进入肝小叶中央静脉周围；4级:纤维结缔组织在全小叶呈多处弥漫性增生，有假小叶形成，并有3级改变。
5.实验结果
(1)一般观察及对肝纤维化大鼠存活率的影响
造模大鼠注射CCl4后明显消瘦，毛色干枯。
各实验组均有动物状态不佳，甚至出现死亡。濒死动物剖腹可见有肝腹水。
实验期间各组动物的存活情况见表1。
表1 MAGLⅡ-11对CCl4所致肝纤维化大鼠存活率的影响
治疗给药1月后MAGLⅡ-11各组的动物存活率明显高于模型组组，该结果提示MAGLⅡ-11对CCl4造成的肝纤维化有保护作用。
(2)对肝纤维化大鼠血清HA、pcIII含量的影响
MAGLⅡ-11治疗给药后对纤维化大鼠血清HA、pcIII的测定结果见表2。
表2 MAGLⅡ-11对CCl4所致肝纤维化大鼠血清指标的影响
与正常对照组比较，#P<0.05，##P<0.01，###P<0.001；
与模型对照组比较，*P<0.05,**P<0.01,***P<0.001；
与秋水仙碱组比较，ΩP<0.05，ΩΩP<0.01。
与正常对照组相比，模型对照组血清HA、pcIII变化有显著性差异。与模型对照组相比，MAGLⅡ-11各组HA含量、pcIII含量有显著性差异。与秋水仙碱组相比，MAGLⅡ-11高剂量组HA含量、pcIII含量有显著性差异。
(3)对大鼠肝脏病理变化的影响
结果如表3所示。
表3 MAGLⅡ-11对CCl4所致肝纤维化大鼠肝纤维化的影响
光镜下HE染色显示正常对照组大鼠的肝小叶结构完整，肝细胞形态正常。模型对照组肝脏小叶中心部明显坏死，其坏死区周围可见脂肪变性的肝细胞，有明显的点状和灶状坏死。而MAGLⅡ-11高低剂量组大鼠肝脏病变程度较模型组均明显减轻。与模型对照组相比，MAGLⅡ-11给药组肝纤维化程度有所减轻，减轻程度与剂量正相关。
实施例2 MAGLⅡ-11对大鼠免疫性肝纤维化的影响
异种血清诱导的免疫性肝纤维化模型是研究肝纤维化治疗药物的重要筛选工具，其主要发病机制类似于Ⅲ过敏反应，与临床病毒性肝炎引起的肝纤维化类似，与化学性肝纤维化模型相比较，该模型与人类肝纤维化的病理机制更为接近，而且肝纤维化形成稳定，肝细胞受损较轻，动物总体状态良好，有利于进行长期的研究。
Wisata大鼠，体重120～160g，全部雄性。
大鼠免疫性肝纤维化模型的制备
参考文献方法，选取健康雄性Wisatr大鼠80只，留取8只作为正常对照，其余大鼠均多点皮下注射9mg·mL-1牛血清白蛋白(BSA)弗氏不完全佐剂乳剂，每次0.5mL，连续注射5次致敏，前两次注射间隔2周，后3次间隔1周。末次致敏后第10天，大鼠眼眶静脉丛采血检测抗体，取BSA抗体阳性大鼠尾静脉攻击注射BSA生理盐水溶液，每次0.4mL，每周2次，剂量由每次2.0mg递增至3.0mg，以后每次增加0.2mg，直至4mg，共攻击注射16次。正常对照组用生理盐水代替BSA。
72只造模大鼠按照体重分为模型组、JZL184组、MAGLⅡ-2组、MAGLⅡ-10组、MAGLⅡ-17组、MAGLⅡ-11低剂量组、MAGLⅡ-11低剂量组、MAGLⅡ-11中剂量组、MAGLⅡ-11高剂量组。
动物给药如下：
指标测定
给药结束后动物禁食不禁水12～16h，70mg·kg-1戊巴比妥钠溶液腹腔注射麻醉，腹主静脉取血，3500r·min-1离心10min，分离上层血清用全自动生化分析仪检测血清AST、ALT、TP、ALB含量；放血处死大鼠，迅速摘取肝脏，称重后剪取0.5g肝组织，按照试剂盒说明书检测Hyp含量
统计处理
数据用
表示，采用SPSS 17.5软件进行分析，组间比较采用ANOVA统计学检验，P<0.05视为差异有统计学意义。
结果
1.MAGLⅡ-11对免疫性肝纤维大鼠血清蛋白和转氨酶的影响
(1)表4结果显示，与对照组相比，模型组血清TP、ALB含量明显降低，ALT、AST含量明显升高；
与模型组相比，MAGLⅡ-11各组均可显著降低血清ALT、AST的含量，升高血清TP、ALB的含量，与模型组比较有统计学意义。
(2)MAGLⅡ-11各组能够显著降低大鼠血清TP、ALB、ALT、AST，结果表明其治疗肝纤维化的效果优于其它给药组。
与JZL184相比，MAGLⅡ-11中、高剂量组降低TP、ALB、ALT、AST，具有显著性差异。
表4 MAGLⅡ-11对免疫性肝纤维化大鼠血清TP、ALB、ALT和AST的影响
与对照组比较，##P<0.01，###P<0.001；
与模型组比较，*P<0.05,**P<0.01,***P<0.001；
与JZL184组比较，ΩP<0.05，ΩΩP<0.01。
2.MAGLⅡ-11对免疫性肝纤维化大鼠肝脏Hyp含量的影响
(1)表5结果显示，与对照组相比，模型组肝脏Hyp含量显著升高；
与模型组相比较，MAGLⅡ-11各组能显著降低肝脏Hyp含量，降低程度与剂量呈正相关。
(2)MAGLⅡ-11各组能够显著降低大鼠肝脏Hyp含量，结果表明其治疗肝纤维化的效果优于其它给药组。
与JZL184相比，MAGLⅡ-11中、高剂量组降低Hyp含量，具有显著性差异。
表5 MAGLⅡ-11对免疫性肝纤维化肝脏大鼠Hyp含量的影响
与对照组比较，##P<0.01，###P<0.001；
与模型组比较，*P<0.05,**P<0.01,***P<0.001；
与JZL184组比较，ΩP<0.05。
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。
Claims (9)
1.MAGLⅡ-11在制备预防或治疗肝纤维化药物中的用途。
2.如权利要求1所述的用途，其特征在于，所述的肝纤维化是化学性肝纤维化或免疫性肝纤维化。
3.如权利要求1所述的用途，其特征在于，所述MAGLⅡ-11在制备治疗和/或预防肝纤维化患病机体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产品中的应用。
4.如权利要求1所述的用途，其特征在于，所述MAGLⅡ-11在制备治疗和/或预防肝纤维化患病机体肝脏Hyp增加的产品中的应用。
5.如权利要求1所述的用途，其特征在于，所述MAGLⅡ-11在制备改善肝纤维化患病机体肝纤维化病理变化的产品中的应用。
6.如权利要求1所述的用途，其特征在于，MAGLⅡ-11的剂型是口服剂型或注射剂型。
7.如权利要求6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。
8.如权利要求6所述的用途，其特征在于，所述注射剂型选自溶液型、混悬液型、乳浊液型或冻干粉。
9.如权利要求6-8任一项所述的用途，其特征在于，所述药物制剂，每一制剂单位中MAGLⅡ-11含量为0.001mg-50mg。
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