Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: New disease-modifying agents for Alzheimer's disease

Munoz-Ruiz, P; Rubio, L; Garcia-Palomero, E; Dorronsoro, I; del Monte-Millan, M; Valenzuela, R; Usan, P; de Austria, C; Bartolini, M; Andrisano, V; Bidon-Chanal, A; Orozco, M; Luque, FJ; Medina, M; Martinez, A

Abstract

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 P-amyloid (M) 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).

Más información

Título según WOS: ID WOS:000233399500018 Not found in local WOS DB
Título de la Revista: JOURNAL OF MEDICINAL CHEMISTRY
Volumen: 48
Número: 23
Editorial: AMER CHEMICAL SOC
Fecha de publicación: 2005
Página de inicio: 7223
Página final: 7233
DOI:

10.1021/jm0503289

Notas: ISI