Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Av. Diagonal, 643, E-08028-Barcelona, Spain +34 934024533 ; +34 934035941 ;
Expert Opin Drug Discov. 2008 Jan;3(1):65-81. doi: 10.1517/17460441.3.1.65.
So far, acetylcholinesterase (AChE) inhibitors have dominated the therapeutic arsenal for Alzheimer's disease. Although conceptually developed as symptomatic drugs, mounting evidence suggests that these compounds can positively modify the disease progression, which has spurred the development of novel classes of AChE inhibitors.
This article reviews the development of novel classes of high affinity AChE inhibitors following a design strategy based on molecular hybridization by stepwise incorporation of different fragments of the known AChE inhibitors (-)-huperzine A and tacrine.
This review covers the existing literature dealing with the design, synthesis and structural and pharmacological characterization of the title compounds.
RESULTS/CONCLUSION: Three novel classes of AChE inhibitors of increasing structural complexity and affinity have been developed, namely huprines, 13-amidohuprines and huprine-tacrine heterodimers. Particularly, huprines and huprine-tacrine heterodimers exhibit a unique profile encompassing both cholinergic and non-cholinergic disease-modifying effects and, thus, constitute promising anti-Alzheimer drug candidates.
到目前为止，乙酰胆碱酯酶 (AChE) 抑制剂一直主导着阿尔茨海默病的治疗策略。尽管这些化合物最初是作为对症药物开发的，但越来越多的证据表明它们可以积极地改变疾病的进程，这促使人们开发了新型 AChE 抑制剂。
本文综述了基于分子杂交设计策略，通过逐步引入已知 AChE 抑制剂（-）石杉碱甲和他克林的不同片段，开发新型高亲和力 AChE 抑制剂的进展。
本综述涵盖了现有文献中涉及标题化合物的设计、合成以及结构和药理学特征的研究。
结果/结论：已经开发出三类结构复杂性和亲和力不断增加的新型 AChE 抑制剂，分别是石杉碱类、13-酰胺石杉碱类和石杉碱-他克林杂合二聚体。特别是，石杉碱类和石杉碱-他克林杂合二聚体具有独特的特性，既具有胆碱能和非胆碱能的疾病修饰作用，因此，它们是有前途的抗阿尔茨海默病药物候选物。
