Huprines for Alzheimer's disease drug development

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.

Keywords::

• 13-amidohuprine
• acetylcholinesterase inhibitor
• Alzheimer's disease
• huprine
• huprine-tacrine heterodimer
• neuroprotective agent
• prion protein antiaggregating agent

Acknowledgments

We thank Prof. A Badia, Prof. V Clos, M Pera and M Ratia from the Departament de Farmacologia, de Terapèutica i de Toxicologia of the Universitat Autònoma de Barcelona (Spain) and Prof. V Andrisano and Dr M Bartolini from the Dipartimento di Scienze Farmaceutiche of the Università di Bologna (Italy) for providing unpublished pharmacological results. We also thank Dr A Bidon-Chanal from the Departament de Fisicoquímica of the Universitat de Barcelona (Spain) for providing the figures of the 3D X-ray structures of the complexes TcAChE-inhibitors that appear in this paper.

Notes