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Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation.
J Med Chem. 2008 Jun 26; 51(12):3588-98.JM

Abstract

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.

Authors+Show Affiliations

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Barcelona, Spain. camps@ub.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18517184

Citation

Camps, Pelayo, et al. "Novel Donepezil-based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-induced Beta-amyloid Aggregation." Journal of Medicinal Chemistry, vol. 51, no. 12, 2008, pp. 3588-98.
Camps P, Formosa X, Galdeano C, et al. Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J Med Chem. 2008;51(12):3588-98.
Camps, P., Formosa, X., Galdeano, C., Gómez, T., Muñoz-Torrero, D., Scarpellini, M., Viayna, E., Badia, A., Clos, M. V., Camins, A., Pallàs, M., Bartolini, M., Mancini, F., Andrisano, V., Estelrich, J., Lizondo, M., Bidon-Chanal, A., & Luque, F. J. (2008). Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. Journal of Medicinal Chemistry, 51(12), 3588-98. https://doi.org/10.1021/jm8001313
Camps P, et al. Novel Donepezil-based Inhibitors of Acetyl- and Butyrylcholinesterase and Acetylcholinesterase-induced Beta-amyloid Aggregation. J Med Chem. 2008 Jun 26;51(12):3588-98. PubMed PMID: 18517184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. AU - Camps,Pelayo, AU - Formosa,Xavier, AU - Galdeano,Carles, AU - Gómez,Tània, AU - Muñoz-Torrero,Diego, AU - Scarpellini,Michele, AU - Viayna,Elisabet, AU - Badia,Albert, AU - Clos,M Victòria, AU - Camins,Antoni, AU - Pallàs,Mercè, AU - Bartolini,Manuela, AU - Mancini,Francesca, AU - Andrisano,Vincenza, AU - Estelrich,Joan, AU - Lizondo,Mònica, AU - Bidon-Chanal,Axel, AU - Luque,F Javier, Y1 - 2008/06/03/ PY - 2008/6/4/pubmed PY - 2008/9/6/medline PY - 2008/6/4/entrez SP - 3588 EP - 98 JF - Journal of medicinal chemistry JO - J Med Chem VL - 51 IS - 12 N2 - A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/18517184/Novel_donepezil_based_inhibitors_of_acetyl__and_butyrylcholinesterase_and_acetylcholinesterase_induced_beta_amyloid_aggregation_ L2 - https://doi.org/10.1021/jm8001313 DB - PRIME DP - Unbound Medicine ER -