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Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease.
J Med Chem. 2005 Nov 17; 48(23):7223-33.JM

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+Show Affiliations

Neuropharma, S.A., Avda. de La Industria 52, 28760 Tres Cantos, Madrid, Spain.No 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

Language

eng

PubMed ID

16279781

Citation

Muñoz-Ruiz, Pilar, et al. "Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-modifying Agents for Alzheimer's Disease." Journal of Medicinal Chemistry, vol. 48, no. 23, 2005, pp. 7223-33.
Muñoz-Ruiz P, Rubio L, García-Palomero E, et al. Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. J Med Chem. 2005;48(23):7223-33.
Muñoz-Ruiz, P., Rubio, L., García-Palomero, E., Dorronsoro, I., del Monte-Millán, M., Valenzuela, R., Usán, P., de Austria, C., Bartolini, M., Andrisano, V., Bidon-Chanal, A., Orozco, M., Luque, F. J., Medina, M., & Martínez, A. (2005). Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. Journal of Medicinal Chemistry, 48(23), 7223-33.
Muñoz-Ruiz P, et al. Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-modifying Agents for Alzheimer's Disease. J Med Chem. 2005 Nov 17;48(23):7223-33. PubMed PMID: 16279781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer's disease. AU - Muñoz-Ruiz,Pilar, AU - Rubio,Laura, AU - García-Palomero,Esther, AU - Dorronsoro,Isabel, AU - del Monte-Millán,María, AU - Valenzuela,Rita, AU - Usán,Paola, AU - de Austria,Celia, AU - Bartolini,Manuela, AU - Andrisano,Vincenza, AU - Bidon-Chanal,Axel, AU - Orozco,Modesto, AU - Luque,F Javier, AU - Medina,Miguel, AU - Martínez,Ana, PY - 2005/11/11/pubmed PY - 2006/1/18/medline PY - 2005/11/11/entrez SP - 7223 EP - 33 JF - Journal of medicinal chemistry JO - J Med Chem VL - 48 IS - 23 N2 - 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). SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16279781/Design_synthesis_and_biological_evaluation_of_dual_binding_site_acetylcholinesterase_inhibitors:_new_disease_modifying_agents_for_Alzheimer's_disease_ L2 - https://doi.org/10.1021/jm0503289 DB - PRIME DP - Unbound Medicine ER -