Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease.
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).
Muñoz-Ruiz
Pilar
P
Neuropharma, S.A., Avda. de La Industria 52, 28760 Tres Cantos, Madrid, Spain.
Rubio
Laura
L
García-Palomero
Esther
E
Dorronsoro
Isabel
I
del Monte-Millán
María
M
Valenzuela
Rita
R
Usán
Paola
P
de Austria
Celia
C
Bartolini
Manuela
M
Andrisano
Vincenza
V
Bidon-Chanal
Axel
A
Orozco
Modesto
M
Luque
F Javier
FJ
Medina
Miguel
M
Martínez
Ana
A
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
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase