CN109503563A - 新型多功能乙酰胆碱酯酶抑制剂及其应用 - Google Patents
新型多功能乙酰胆碱酯酶抑制剂及其应用 Download PDFInfo
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Abstract
本发明公开了一种新型多功能乙酰胆碱酯酶抑制剂，2‑(5‑((4‑甲基哌啶‑1‑基)甲基)‑1,3,4‑噁二唑‑2‑巯基)‑1‑对甲基苯乙酮，及其在制备预防和/或治疗AChE相关的疾病的药物、制备预防和/或治疗Aβ聚集相关的疾病的药物、制备预防和/或治疗Aβ诱导的神经损伤所导致疾病的药物中的应用，本发明的化合物，能够抑制AChE，并且可以效抑制Aβ聚集、对Aβ诱导的神经损伤具有明显的神经保护作用，能够用于制备预防和/或治疗AD等相关神经退行性疾病的药物。
Description
技术领域
本发明涉及一种新型多功能乙酰胆碱酯酶抑制剂及其应用，2-(5-((4-甲基哌啶-1-基)甲基)-1,3,4-噁二唑-2-巯基)-1-对甲基苯乙酮作为乙酰胆碱酯酶抑制剂的应用。
背景技术
阿尔茨海默症(Alzheimer’s Disease，AD)是一种进行性发展的、多因素、致死性神经退行性疾病。临床表现为认知障碍、患者行为异常。根据世界阿尔茨海默症报告，2015年全球AD患病人数为四千六百万，预期到2050年患病人数将达到1.3亿。
AD病因及发病机制极尚不清楚，而胆碱功能障碍、淀粉样蛋白-β（Aβ）聚集和tau蛋白质磷酸化被认为在AD的发展起着重要的作用。然而，靶向Aβ和tau蛋白质药物的临床试验均以失败而告终，目前通过提高乙酰胆碱水平来提高胆碱能神经传递仍然是目前AD最有效的治疗手段。脑中的乙酰胆碱主要有乙酰胆碱酯酶水解，因此，AChE抑制剂是被研究的最多且临床上最为普遍认同的一线治疗AD药物，如他克林、多奈哌齐、雷司替明和加兰他敏。然而，这些AChE抑制剂治疗效果均不佳，只能在病情发展的特定阶段有限的缓解或稳定病情且伴有严重副作用。因此亟需开发新型疗效好、副作用低的AChE抑制剂。
在新药开发过程中，虚拟筛选被证明是一种非常有效的药物先导物发现手段。我们课题组对商业化合物库（SPECS）进行了虚拟筛选，后期通过活性筛选得到了一个化合物，能够抑制乙酰胆碱酯酶，并且可有效抑制Aβ聚集、对Aβ诱导的神经损伤具有明显的神经保护作用，能够作为新型多功能乙酰胆碱酯酶抑制剂，具有发展成为AD等神经退行性疾病药物的良好应用前景。
发明内容
本发明的目的是提供一种新型多功能AChE抑制剂。
本发明的第一方面，提供式了如式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药：
2-(5-((4-甲基哌啶-1-基)甲基)-1,3,4-噁二唑-2-巯基)-1-对甲基苯乙酮
。
本发明的第二方面，一种药物组合物，所述药物组合物包含第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药；和药学上可接受的载体。
本发明的第三方面，提供了第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药用途，用于：
（i）制备AChE抑制剂；
（ii）制备预防和/或治疗AChE相关的疾病的药物；
（iii）制备Aβ聚集药物；
（iv）制备预防和/或治疗Aβ聚集相关的疾病的药物；
（v）制备对Aβ诱导的神经损伤具有明显的神经保护作用的药物；
（vi）制备预防和/或治疗Aβ诱导的神经损伤所导致疾病的药物。
药学上可接受的载体必须可与配方的其他成分兼容，且不会对其接受者有害，一般为适当载剂、稀释剂及赋形剂是为本领域技术人员所公知且包括诸如碳水化合物、蜡、水溶性及/或泡胀性聚合物、亲水性或疏水性材料、明胶、油、溶剂、水及类似物。所使用的特定载剂、稀释剂或赋形剂将取决于给予本发明化合物的方式及目的。溶剂通常是基于本领域技术人员所认为安全给予哺乳动物的溶剂(GRAS)而选择。通常，安全溶剂为无毒水性溶剂(诸如水)及其他可溶于水或与水可混溶的无毒溶剂。适当水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400或PEG300)等及其混合物。还可包括一或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助滑剂、加工助剂、着色剂、甜味剂、香料、调味剂及其他提供药物(即本发明化合物或其医学组合物)精美外观或有助于制造药物产品(即用于制备药剂)的已知添加剂。
有益效果
本发明的化合物，能够抑制AChE，并且可以效抑制Aβ聚集、对Aβ诱导的神经损伤具有明显的神经保护作用，能够用于制备预防和/或治疗AD等相关神经退行性疾病的药物。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
本申请的发明人经过对商业化合物库的虚拟筛选及活性研究，发现了一种多功能AChE抑制剂，能够有效抑制AChE，并且可以效抑制Aβ聚集、对Aβ诱导的神经损伤具有明显的神经保护作用。在此基础上，完成了本发明。
本发明中，式I化合物是指具有如下式I所示的化合物：
。
实施例1 化合物对AChE酶活的影响
乙酰胆碱酯酶（AChE）、作为底物的碘化硫代乙酰胆碱（ATC）和作为显色剂的5,5-二硫双（2-硝基苯甲酸）（DTNB）均购自Sigma。AChE抑制活性测定参考Ellan等报道的方法进行（Ellman, G. L. et al. Biochem. Pharmacol. 1961, 7, 88.）。96孔板每孔加入40 μL的磷酸缓冲液（pH = 8.0），然后将0.39、0.78、1.56、3.125、6.25、12.5、25、50和100 μM的10 μL待测化合物溶液或空白对照加入到对应的空中，随后加入10 μL的AChE，置于37°C摇床孵育5 min。加入20 μL的DTNB溶液，再置于37°C摇床孵育5 min，随后加入10 μL的底物ATC置于37°C摇床孵育3 min后，酶标仪测定412 nm处的吸光度，计算待测化合物对AChE的抑制率。根据抑制曲线求得化合物的IC50值(抑制酶活力50%时的抑制剂浓度)，实验结果如表1所示。
表1. 化合物对AChE酶活性抑制活性
实施例2 化合物对Aβ聚集的影响
用DMSO（Sigma）将Aβ1-42（吉尔生物化学有限公司，中国上海）溶解，制备成200μM的储备溶液。将储备溶液以13,500 rpm的速度离心10分钟取上述储备液的上清液用于实验。用DMSO将待测化合物溶解成0.8 mM。通过测量ThT的荧光发射间接测试化合物对Aβ聚集的抑制能力。先将76μL磷酸盐缓冲盐水（pH 7.4的PBS）加入到96孔板孔板中，再向其中加入2μL0.8 mM化合物和2μL 200μM Aβ1-42，在室温下孵育24小时后，向反应溶液中加入80 μL 5μMThT溶液（用pH 8.5的50 mM甘氨酸-NaOH缓冲液溶解THT）。在酶标仪的490 nm处测量荧光发射，激发波长为390 nm。通过进行三次独立实验记录相同的光谱。比较荧光强度，通过以下等式计算％抑制：100 - [（Fi-Fb）/（Fo-Fb）×100]其中，Fi，Fo和Fb是指有抑制剂、THT和Aβ1-42存在的条件下Aβ聚集获得的荧光强度；有Aβ1-42和THT存在下、但没有抑制剂条件下获得的荧光强度；空白组仅包含THT。多奈哌齐为阳性对照，加兰他敏作为阴性对照。实验结果如表2所示。
表2. 化合物对Aβ聚集抑制活性
实验结果表明，化合物I对Aβ1-42聚集具有明显的抑制活性，且作用效果优于阳性对照药物多奈哌齐。
实施例3 化合物对Aβ1-42诱导SH-SY5Y神经细胞损伤的保护作用
SH-SY5Y购自美国国立细胞库，采用含10%胎牛血清的DMEM培养基，于37℃、5% CO2饱和湿度的培养箱中常规培养。以2-2.5×105个细胞/mL的密度接种于96孔板中，培养24 h后进行实验。更换新鲜的培养液，并将细胞分为正常组、Aβ1-42损伤模型组、待测化合物预处理组。待测化合物处理组分别加入式I化合物（10 µM），EGCG阳性对照组加入EGCG（茶多酚），Aβ组和正常组不进行添加。在培养2 h后，除正常组外其他各组加入终浓度10 µM的Aβ1-42，继续培养24h，加入MTT（终浓度0.5 mg/ml），培养3 h后，在490 nm波长下检测吸光度值的变化。实验结果如表3所示。
表3. 化合物对Aβ1-42诱导SH-SY5Y神经细胞损伤的保护作用
实验结果表明，化合物I对Aβ1-42诱导的SH-SY5Y神经细胞损伤具有显著的保护作用，其作用效果优于阳性对照药物EGCG。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (8)
1.一种乙酰胆碱酯酶抑制剂，如式I所示的化合物：
。
2.一种式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药、和药学上可接受的载体，在制备预防和/或治疗AChE相关的疾病的药物中的应用。
3.根据权利要求2所述的应用，其特征在于，预防和/或治疗AChE相关的疾病的药物为乙酰胆碱酯酶抑制剂的药物。
4.一种式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药、和药学上可接受的载体，在制备预防和/或治疗Aβ聚集相关的疾病的药物中的应用。
5.根据权利要求4所述的应用，其特征在于，预防和/或治疗Aβ聚集相关的疾病的药物为抑制淀粉样蛋白-β聚集的药物。
6.一种式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药、和药学上可接受的载体，在制备预防和/或治疗Aβ诱导的神经损伤所导致疾病的药物中的应用。
7.根据权利要求6所述的应用，其特征在于，制备预防和/或治疗Aβ诱导的神经损伤所导致疾病的药物为对Aβ诱导的神经损伤具有明显的神经保护作用的药物。
8.一种式I所示的化合物，或其药学上可接受的盐、水合物、溶剂化物或前药、和药学上可接受的载体，在制备预防和/或治疗AD等相关神经退行性疾病的药物中的应用。
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