title: Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease.
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 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).
authors.affiliation: Neuropharma, S.A., Avda. de La Industria 52, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Muñoz-Ruiz
authors.forename: Laura
authors.initials: L
authors.lastname: Rubio
authors.forename: Esther
authors.initials: E
authors.lastname: García-Palomero
authors.forename: Isabel
authors.initials: I
authors.lastname: Dorronsoro
authors.forename: María
authors.initials: M
authors.lastname: del Monte-Millán
authors.forename: Rita
authors.initials: R
authors.lastname: Valenzuela
authors.forename: Paola
authors.initials: P
authors.lastname: Usán
authors.forename: Celia
authors.initials: C
authors.lastname: de Austria
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Axel
authors.initials: A
authors.lastname: Bidon-Chanal
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Miguel
authors.initials: M
authors.lastname: Medina
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002417:Cattle; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D019281:Dimerization; D015195:Drug Design; D004912:Erythrocytes / Q000201:enzymology; D005470:Fluorometry; D006801:Humans; D008958:Models, Molecular; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase