Diego Muñoz-Torrero1, Pelayo Camps. 1. 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 ; dmunoztorrero@ub.edu +34 934024536 ; +34 934035941 ; camps@ub.edu.
Abstract
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.
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.
Authors: Julien Defaux; Marta Sala; Xavier Formosa; Carles Galdeano; Martin C Taylor; Waleed A A Alobaid; John M Kelly; Colin W Wright; Pelayo Camps; Diego Muñoz-Torrero Journal: Bioorg Med Chem Date: 2011-01-21 Impact factor: 3.641
Authors: Eva Mezeiova; Jan Korabecny; Vendula Sepsova; Martina Hrabinova; Petr Jost; Lubica Muckova; Tomas Kucera; Rafael Dolezal; Jan Misik; Katarina Spilovska; Ngoc Lam Pham; Lucia Pokrievkova; Jaroslav Roh; Daniel Jun; Ondrej Soukup; Daniel Kaping; Kamil Kuca Journal: Molecules Date: 2017-07-28 Impact factor: 4.411