Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.
Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimer's disease progression.
Camps
Pelayo
P
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
Formosa
Xavier
X
Galdeano
Carles
C
Gómez
Tània
T
Muñoz-Torrero
Diego
D
Ramírez
Lorena
L
Viayna
Elisabet
E
Gómez
Elena
E
Isambert
Nicolás
N
Lavilla
Rodolfo
R
Badia
Albert
A
Clos
M Victòria
MV
Bartolini
Manuela
M
Mancini
Francesca
F
Andrisano
Vincenza
V
Bidon-Chanal
Axel
A
Huertas
Oscar
O
Dafni
Thomai
T
Luque
F Javier
FJ
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000077265:Donepezil; D055808:Drug Discovery; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013619:Tacrine / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D011804:Quinolines; D013619:Tacrine; D000077265:Donepezil; C037219:quinoline; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human