Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease.
|Title||Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Muñoz-Ruiz, Pilar, Rubio Laura, García-Palomero Esther, Dorronsoro Isabel, del Monte-Millán María, Valenzuela Rita, Usán Paola, de Austria Celia, Bartolini Manuela, Andrisano Vincenza, Bidon-Chanal Axel, Orozco Modesto, F Luque Javier, Medina Miguel, and Martínez Ana|
|Journal||J Med Chem|
|Date Published||2005 Nov 17|
|Keywords||Acetylcholinesterase, Alzheimer Disease, Amyloid beta-Peptides, Animals, Binding Sites, Butyrylcholinesterase, Cattle, Cell Line, Cholinesterase Inhibitors, Dimerization, Drug Design, Erythrocytes, Fluorometry, Humans, Models, Molecular, Nootropic Agents, Protein Binding, Structure-Activity Relationship, Tacrine, Tumor|
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).