Research Strategies Developed for the Treatment of Alzheimer’s Disease. Reversible and Pseudo-Irreversible Inhibitors of Acetylcholinesterase: Structure-Activity Relationships and Drug Design
Pp. 426-477 (52)
Mauricio Alcolea-Palafox, Paloma Posada-Moreno, Ismael Ortuño- Soriano, José L. Pacheco-del-Cerro, Carmen Martínez-Rincón, Dolores Rodríguez-Martínez and Lara Pacheco-Cuevas
Although several research strategies have been developed in the last decades,
the current therapeutic options for the treatment of Alzheimer’s disease are limited to
three acetylcholinesterase inhibitors: galantamine, donepezil and rivastigmine. However,
they have only offered a modest improvement in memory and cognitive function.
Moreover, these drugs show side effects, and relatively low bioavailability among other
problems. These features limit their use in medicine and they lead to a great demand for
discovering new acetylcholinesterase inhibitors. In addition to its important role in
cholinergic neurotransmission, acetylcholinesterase also participates in other functions
related to neuronal development, differentiation, adhesion and amyloid-β processing.
Acetylcholinesterase accelerates amyloid-β aggregation and this effect is sensitive to
peripheral anionic site blockers. Both features have lead to the development of dual
inhibitors of both catalytic active and peripheral anionic sites. These compounds are
promising disease-modifying Alzheimer’s disease drug candidates. On the other hand,
due to the pathological complexity of Alzheimer’s disease, multifunctional molecules
with two or more complementary biological activities may represent an important
advance for the treatment of this disease. All these features are described in detail in the
Alzheimer’s disease, donepezil, galantamine, huperzine, huprines,
infractopicrin, inhibitors AChE, ladostigil, physostigmine derivatives, rivastigmine,
tacrine, tacrine hybrid, tacripyrines and donepezil hybrids, TAK-147.
Chemical-Physics Department, Chemistry Faculty, Complutense University of Madrid, Spain.