以复合物晶体结构为基础的双位点AChE抑制剂的结构改造

发布时间：2018-03-21 16:54

本文选题：乙酰胆碱酯酶　切入点：β淀粉样肽　出处：《复旦大学》2014年硕士论文　论文类型：学位论文

【摘要】：阿尔茨海默病是一种以进行性记忆减退、智力衰退、语言行为障碍甚至意识丧失为主要症状的神经退行性疾病。阿尔茨海默病的具体发病机制还未被完全研究清楚,主要认为“β淀粉样肽(Aβ)沉积”和“tau蛋白的异常磷酸化”是导致阿尔茨海默病发病的两个重要机制,而“胆碱能神经损伤”是导致阿尔茨海默病患者认知和行为障碍的主要病理因素。现在用于阿尔茨海默病治疗的药物大多数都是乙酰胆碱酯酶(AChE)抑制剂。使用AChE抑制剂只能改善阿尔茨海默病患者的症状,并不能彻底治愈或改变阿尔茨海默病的病理过程。目前AChE抑制剂的研究主要集中于寻找更加安全或具有多重作用的AChE抑制剂。本文基于已发现的双位点AChE抑制剂XQ509,针对XQ509口服生物利用度差和抑制邮聚集活性相对较低的缺点,对XQ509复合物晶体结构信息进行分析,并结合计算机辅助药物设计软件,设计并合成了三个系列的目标化合物。第一系列化合物以改善口服生物利用度为目标,用杂原子或极性基团取代-Q509的全碳连接链。第二、第三系列化合物以提高抑制Aβ聚集活性为目标,用不同长度的连接链连接(-)-美普他酚和多奈哌齐茚酮结构或邻苯二甲酰亚胺结构。对三个系列目标化合物进行AChE抑制活性测试。第一系列目标化合物测试结果显示杂原子或极性基团取代连接链对化合物的活性有较大的影响。这可能是因为连接链需要有一定的柔性来达到最优的结合构象,在某些位置增加杂原子可能导致化合物分子不能扭转至最优的构象,从而造成化合物抑制活性的下降。这一系列活性最好的化合物(1b、1e)的IC50分别达到4.4 nM和4.3 nM,与化合物XQ509 (IC505.7nM)相当。第二系列茚酮类目标化合物测试结果显示连接链长度与活性密切相关,最适长度为5-6碳。这一系列活性最好的化合物(2d、2e)的IC50分别达到12 nM和14 nM,均优于多奈哌齐(IC5055nM)。第三系列目标化合物测试结果显示邻苯二甲酰亚胺类化合物的活性相对较差。对AChE抑制活性较高的化合物(1b、1e、2d、2e)进行初步的AChE诱导Aβ聚集抑制活性试验,结果发现这些化合物抗Aβ聚集的活性相较XQ509并未提高。进一步分子对接和构象分析发现在外周阴离子位点的结合差异明显,且不牢固。其中活性最高的化合物1b在50μM浓度下对Aβ聚集的抑制率为44.8%,低于XQ509(抑制率58.4%)。目标化合物经计算机辅助药物设计软件ADME/T性质预测,预示水溶解度、口服吸收以及血脑屏障透过率均较好。大鼠体内口服生物利用度初步评价结果表明,化合物(1b、1e、2d、2e)的口服吸收并没有得到提高,甚至出现下降,特别是茚酮类化合物2d。其中口服生物利用度最高的化合物1b,绝对生物利用度为5.54%,略低于XQ509(F=8.40%)。通过进一步的测试发现此类化合物的肝微粒体代谢稳定性较差,可能是导致口服生物利用度较差的另外一个因素。在所有目标化合物中1b具有与XQS09最接近的体外AChE抑制活性、抗Aβ聚集活性和代谢稳定性,口服生物利用度较XQ509差别不大,极性羟基的引入可能对药物的组织分布有改善作用,值得进一步研究。
[Abstract]:Alzheimer's disease is a progressive memory loss, mental decline, language behavior disorders and even loss of consciousness as the main symptoms of the neurodegenerative diseases. The pathogenesis of Alzheimer's disease has not been fully understood, mainly that beta amyloid (A beta) deposition and abnormal phosphorylation of tau protein "is the two important mechanisms of the pathogenesis of Alzheimer's disease, and cholinergic nerve injury is the main pathological disease and cognitive and behavior disorders of Alzheimer's factors. Now the majority of drugs for treatment of Alzheimer's disease are acetylcholinesterase (AChE) inhibitors. AChE inhibitors can improve the symptoms of Alzheimer's disease patients, and pathological process can not be completely cured or change of Alzheimer's disease. At present, the study of AChE inhibitors mainly focused on looking for safer or with multiple AChE inhibitor. This paper has found two locus AChE inhibitors based on XQ509 XQ509 for poor oral bioavailability and inhibit post aggregation activity is relatively low the shortcomings of complex structure of XQ509 information analysis, and combined with the computer aided drug design software design and the target compounds synthesized three series of the first. A series of compounds to improve oral bioavailability as the goal, with heteroatom or polar groups substituted carbon chain connecting -Q509. Second, third series of compounds to improve the inhibition of A beta aggregation activity as the goal, with different length of the connecting link (-) - meptazinol and donepezil indone structure or phthalate two methyl imide structure. The AChE inhibitory activity of three series of target compounds. The first series of target compounds test results show that the heteroatom or polar groups substituted for connecting chain compounds Has great influence on the activity. This may be because the connection chain needs to have certain flexibility to achieve optimal binding conformation, increasing heteroatoms in certain positions may lead to the optimal conformation compounds can not be reversed, resulting in decrease in compound inhibitory activity. Compounds of this series of the best activity (1b, 1e) IC50 respectively. Up to 4.4 nM and 4.3 nM, and compound XQ509 (IC505.7nM). The second series of indenone compounds test results show that the connection chain length and activity is closely related to the optimal length of 5-6 carbon compounds. This series of the best activity (2D, 2e) IC50 were respectively 12 nM and 14 nM were better than that of donepezil (IC5055nM). Third compounds of series test results show that the adjacent benzene two phthalimide compounds activity is relatively poor. Higher inhibitory activity of compounds AChE (1b, 1e, 2D, 2e) of AChE induced by A Inhibitory activity test results showed that anti A beta aggregation, these compounds beta aggregation activity compared with XQ509 did not improve. Further molecular docking and conformational analysis found in the peripheral anionic binding sites significantly different, and not strong. The compounds that inhibit the activity of 1b is the highest aggregation of A beta in 50 M concentration rate is 44.8%. Less than XQ509 (inhibition rate 58.4%). Prediction of target compounds by computer aided drug design software ADME/T properties, water solubility prediction, oral absorption and blood brain barrier permeability in rats. Good oral bioavailability of preliminary evaluation results showed that the compounds (1b, 1e, 2D, 2e) of the oral absorption and no improvement, or even decline, especially the indenone compound 2D. the oral bioavailability of the highest compound 1b, absolute bioavailability was 5.54%, slightly lower than XQ509 (F=8.40%). Through further testing found this Liver microsomal metabolism stability of compounds may lead to poor oral bioavailability is another factor of poor. In all the target compounds in 1b is the most close to XQS09 in vitro AChE inhibitory activity, anti A beta aggregation activity and metabolic stability, oral bioavailability is XQ509 little difference, introducing the polar hydroxyl group may the drug distribution effect, it is worthy of further study.

【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91

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