新型多靶向他克林衍生物的研究进展  

Progress in Novel Multi-target-directed Tacrine Derivatives

作　　者：陈瑶[1] 孙昊鹏[2] 李伟[1] 

机构地区：[1]南京中医药大学药学院,江苏南京210023 [2]中国药科大学药学院,江苏南京210009

出　　处：《药学进展》2014年第9期656-664,共9页Progress in Pharmaceutical Sciences

基　　金：南京中医药大学青年自然科学基金(No.13XZR21)

摘　　要：阿尔茨海默病(AD)是一种常见的神经退行性疾病,不仅严重威胁着老年人的身心健康,更给整个社会医疗卫生系统带来沉重负担,因此,设计与开发安全有效的抗AD药物,一直是医药研究领域的热点。AD病因尚不明确且致病机制极为复杂,仅针对单一靶标治疗难以获得理想疗效,因此一药多靶成为了抗AD药物研发的新方向。目前临床上最为成功的抗AD药物为乙酰胆碱酯酶(ACh E)抑制剂,尽管第一代ACh E抑制剂他克林因严重的毒副作用而撤市,但其结构简单,活性明确,在用于多靶向设计的结构改造方面具有独特优势,可作为理想的活性片段,引入多靶向抗AD药物的整体分子骨架中。通过一些代表性案例,综述近年来基于他克林结构而设计多靶向抗AD药物的研究进展,探讨其设计思路,为新型多靶向他克林衍生物的研发提供参考。Alzheimer＇s disease（AD）,one of the most common neurodegenerative diseases,not only threatens the health of elderly people,but also burdens the whole social medical and health system. As a result,the design and development of effi cacious and safe anti-AD agents has become a hotspot in the fi eld of pharmaceutical research. Till now,the complicated pathogenesis of AD has not been elucidated,indicating that the treatment only for a single target is diffi cult to fully achieve therapeutic effects,and therefore,the multi-target-directed agents are considered to be the new trend for the development of anti-AD agents. Acetylcholinesterase（AChE） inhibitors are the most successful compounds in the clinical treatment of AD at present time. Although tacrine,the fi rst generation of AChE inhibitors,has been withdrawn due to severe toxicity,its structure is simple,its activity is clear and it shows its superiority in the structural modifi cation for the design of complicated multi-target-directed molecules. Herefrom,tacrine as the ideal active fragment could be introduced into the overall molecular skeletons of the multi-target-directed anti-AD agents. With some typical cases,the advances in the design of multi-target-directed anti-AD agents based on tacrine structure were reviewed and the design ideas were discussed so as to provide the reference for the further development of novel multi-target-directed tacrine derivatives.

关 键 词：阿尔茨海默病 乙酰胆碱酯酶抑制剂 他克林 多靶向衍生物 分子设计 

分 类 号：R749.16[医药卫生—神经病学与精神病学]