Huprines for Alzheimer's disease drug development

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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.