CN112294815B - 化合物bay-876在制备治疗和/或预防肝损伤药物中的用途 - Google Patents
化合物bay-876在制备治疗和/或预防肝损伤药物中的用途 Download PDFInfo
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Abstract
本发明公开了化合物BAY‑876在制备治疗和/或预防肝损伤药物中的用途，可以制成一种新型的护肝药物。本发明进行了大量实验研究，使用脂多糖(lipopolysaccharides,LPS)/D‑氨基半乳糖(D‑Galactosamine,D‑Gal)建立急性肝损伤小鼠模型。研究结果表明化合物BAY‑876能够明显降低肝损伤小鼠血浆谷丙转氨酶、谷草转氨酶水平，降低TNF‑α、IL‑6等炎症因子水平，显著改善肝组织损伤，减轻肝细胞凋亡，具有显著的防治肝损伤的功效。本发明为肝损伤治疗提供了新的候选药物BAY‑876。
Description
技术领域
本发明涉及一种化合物BAY-876在制备治疗和/或预防肝损伤药物中的用途，属于医药技术领域。
背景技术
肝脏是人体重要的代谢器官，发挥着至关重要的生理作用。病毒、药物、毒物、酒精等各种原因可导致急性肝损伤，严重者可引起肝功能衰竭，诱发多器官功能障碍甚至死亡。急性肝损伤的机制被认为是与免疫失衡密切相关，活化的枯否细胞分泌的大量的促炎因子，如肿瘤坏死因子-α(tumor necrosis factor alpha,TNF-α)、白细胞介素-6(Interleukin6,IL-6)诱发的肝细胞大量坏死和凋亡是疾病发生发展的主要致病机制。
目前临床上复方甘草酸苷、双环醇片等药物虽有一定的效果，但尚缺乏特效的治疗药物，因此急需研发治疗肝损伤的药物。
发明内容
本发明的主要目的，在于提供BAY-876在制备预防/治疗肝损伤药物中的用途。本发明涉及的化合物BAY-876的化学结构式如下：
其化学式为C24H16F4N6O2，分子量为496.42；
该化合物是是葡萄糖转运蛋白1的抑制剂；经检索目前尚未见化合物BAY-876在防治肝损伤中的医用用途。
其中，优选地，本发明所述的肝损伤为急性肝损伤。
优选地，所述药物中还包含药学上可接受的载体。
优选地，所述药学上可接受的载体选自下组：稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的至少一种。
优选地，BAY-876，其药学上可接受的盐、溶剂合物、立体异构体、互变异构体或所述药物，配制为片剂、散剂、丸剂、注射剂、胶囊剂、膜剂、栓剂、膏剂或冲剂。
本技术方案与背景技术相比，具有如下优点：
本发明结果表明化合物BAY-876能够明显降低肝损伤小鼠血浆谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)水平，降低TNF-α、IL-6等炎症因子水平，显著改善肝组织损伤，减轻肝细胞凋亡，具有显著的防治肝损伤的功效。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为BAY-876对肝损伤小鼠转氨酶水平的影响。
图2为BAY-876肝损伤小鼠炎症因子的影响。
图3为BAY-876对肝损伤小鼠肝组织病理的影响。
图4为BAY-876对肝损伤小鼠肝细胞凋亡的影响。
具体实施方式
1.实验材料
1.1实验用药物及试剂
BAY-876购自Selleckchem公司。
1.2实验动物及饲养
雄性C57BL/6小鼠，18-22g，雄性，由上海吉辉实验动物饲养有限公司提供，合格证号：20170012002547。饲养条件：室温20±2℃，湿度50％±5％，明暗交替，光照适度，通风洁净良好，自由饮水与进食。
2.方法
2.1急性肝损伤小鼠模型造模方法
采用C57BL/6小鼠，预先饲养一周，腹腔注射脂多糖(lipopolysaccharides,LPS)/D-氨基半乳糖(D-Galactosamine,D-Gal)复制急性肝损伤小鼠模型。
2.2实验分组
C57小鼠24只，随机分为3组，每组8只。分别为正常对照组，模型组，BAY-876干预组。模型组及BAY-876干预组采用LPS(10μg/kg)及D-Gal(700mg/kg)造模。正常对照组及模型组给予花生油(含1％二甲基亚砜)；BAY-876 0.1mg/kg溶于花生油(含1％二甲基亚砜)，于上述方法造模前0.5h腹腔注射。实验终点时处死小鼠，留取血及肝组织备用。
2.3血浆生化检测
取小鼠血浆，使用商品化试剂盒检测ALT、AST水平。
2.4炎性因子检测
取小鼠血浆，使用ELISA试剂盒，检测血浆中TNF-α、IL-6水平。
2.5肝组织HE染色
取小鼠肝组织标本，在4％多聚甲醛中固定，使用石蜡包埋、切片。使用苏木精-伊红染色，通过200倍光学显微镜观察肝组织病理变化。
2.6 TUNEL法细胞凋亡检测：肝组织石蜡切片，按TUNEL试剂盒说明的步骤进行染色。染色后细胞核棕黄(褐)为凋亡细胞，高倍镜下随机选取20个视野计数凋亡细胞数目。
3.统计分析
数据采用
表示，采用t检验或单因素方差分析进行检验，p<0.05为差异有统计学意义。
4.实验结果
4.1 BAY-876对肝损伤小鼠转氨酶水平的影响。
转氨酶水平可直接反映急性肝损伤严重程度，模型组小鼠血浆ALT和AST水平与正常对照组比较，明显升高，差异具有显著性；BAY-876干预组与模型组比较，ALT和AST水平明显下降。BAY-876显著降低了急性肝损伤小鼠血浆转氨酶水平(如图1)。
4.2 BAY-876肝损伤小鼠炎症因子的影响。
LPS/D-Gal处理后，模型组小鼠血浆TNF-α和IL-6水平显着高于正常对照组。BAY-876干预组血浆TNF-α和IL-6水平显着低于模型组。BAY-876显著抑制了急性肝损伤小鼠TNF-α、IL-6炎症因子产生(如图2)。
4.3 BAY-876对肝损伤小鼠肝组织病理的影响。
模型组小鼠肝组织切片的形态学结果显示：小鼠的肝小叶结构破坏，肝脏充血、出血，大量肝细胞变性、坏死伴有炎性细胞浸润。BAY-876干预后，急性肝损伤小鼠肝脏充血和肝细胞坏死等病理改变明显减轻。BAY-876可明显减轻急性肝损伤小鼠肝组织形态学异常(如图3)。
4.4 BAY-876对肝损伤小鼠肝细胞凋亡的影响。
模型组小鼠的肝组织凋亡细胞与正常对照组比较，显著增多；给予BAY-876后，凋亡细胞的数量显著减少。BAY-876显著减轻了急性肝损伤小鼠的肝细胞凋亡(如图4)。
使用LPS/D-Gal组合建立的急性肝损伤动物模型，已被用作研究临床肝病机制和评估肝脏保护剂作用的成熟模型。以上药效学试验结果显示，化合物BAY-876能够显著降低模型小鼠血浆转氨酶水平，显著减轻肝组织病理损伤，能显著抑制TNF-α、IL-6炎症因子水平，减轻LPS/D-Gal诱导的肝细胞凋亡。本实验研究结果证明，化合物BAY-876具有很好的防治肝损伤的功效。
以上实施方式只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人了解本发明内容并加以实施，并不能以此限制本发明的保护范围，凡根据本发明精神实质所做的等效变化或修饰，都应涵盖在本发明的保护范围内。
Claims (4)
1.化合物BAY-876或其药学上可接受的盐在制备治疗和/或预防肝损伤药物中的用途，所述的肝损伤为急性肝损伤，其中，化合物BAY-876的化学结构式如下：
2.根据权利要求1所述的用途，其特征在于：所述药物中还包含药学上可接受的载体。
3.根据权利要求2所述的用途，其特征在于：所述药学上可接受的载体选自下组：填充剂、粘合剂、润湿剂、崩解剂、润滑剂中的至少一种。
4.根据权利要求1或2所述的用途，其特征在于：BAY-876或其药学上可接受的盐配制为片剂、散剂、丸剂、注射剂、胶囊剂、膜剂、栓剂、膏剂或冲剂。
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