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Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-Modifying Agents for Alzheimer's Disease

2005; American Chemical Society; Volume: 48; Issue: 23 Linguagem: Inglês

10.1021/jm0503289

1520-4804

Pilar Muñoz-Ruiz, Laura Rubio, Esther Garcı́a-Palomero, Isabel Dorronsoro, María del Monte‐Millán, Rita Valenzuela, Paola Usán, Celia de Austria, Manuela Bartolini, Vincenza Andrisano, Axel Bidon‐Chanal, Modesto Orozco, F. Javier Luque, Miguel Medina, Ana Martı́nez,

Alzheimer's disease research and treatments

New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as new potent drugs that may simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting the beta-amyloid (A beta) peptide aggregation through binding to both catalytic and peripheral sites of the enzyme. Particularly, compounds 5 and 6 emerged as the most potent heterodimers reported so far, displaying IC50 values for AChE inhibition of 20 and 60 pM, respectively. More importantly, these dual AChE inhibitors inhibit the AChE-induced A beta peptide aggregation with IC50 values 1 order of magnitude lower than that of propidium, thus being the most potent derivatives with this activity reported up to date. We therefore conclude that these compounds are very promising disease-modifying agents for the treatment of Alzheimer's disease (AD).