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Title: | Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound |
Author: | Sola, Irene Viayna, Elisabet Gómez Nadal, Tània Galdeano Cantador, Carlos Cassina, Matteo Camps García, Pelayo Romeo, Margherita Diomede, Luisa Salmona, Mario Franco, Pilar Schaeffer, Mireille Colantuono, Diego Robin, David Brunner, Daniela Taub, Nicole Hutter-Paier, Birgit Muñoz-Torrero López-Ibarra, Diego |
Keywords: | Malaltia d'Alzheimer Disseny de medicaments Química farmacèutica Dianes farmacològiques Ratolins (Animals de laboratori) Alzheimer's disease Drug design Pharmaceutical chemistry Drug targeting Mice (Laboratory animals) |
Issue Date: | 10-Mar-2015 |
Publisher: | MDPI |
Abstract: | We describe the multigram synthesis and in vivo efficacy studies of a donepezil‒huprine hybrid that has been found to display a promising in vitro multitarget profile of interest for the treatment of Alzheimer's disease (AD). Its synthesis features as the key step a novel multigram preparative chromatographic resolution of intermediate racemic huprine Y by chiral HPLC. Administration of this compound to transgenic CL4176 and CL2006 Caenorhabditis elegans strains expressing human Aβ42, here used as simplified animal models of AD, led to a significant protection from the toxicity induced by Aβ42. However, this protective effect was not accompanied, in CL2006 worms, by a reduction of amyloid deposits. Oral administration for 3 months to transgenic APPSL mice, a well-established animal model of AD, improved short-term memory, but did not alter brain levels of Aβ peptides nor cortical and hippocampal amyloid plaque load. Despite the clear protective and cognitive effects of AVCRI104P4, the lack of Aβ lowering effect in vivo might be related to its lower in vitro potency toward Aβ aggregation and formation as compared with its higher anticholinesterase activities. Further lead optimization in this series should thus focus on improving the anti-amyloid/anticholinesterase activity ratio. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.3390/molecules20034492 |
It is part of: | Molecules, 2015, vol. 20, num. 3, p. 4492-4515 |
URI: | http://hdl.handle.net/2445/65727 |
Related resource: | http://dx.doi.org/10.3390/molecules20034492 |
ISSN: | 1420-3049 |
Appears in Collections: | Articles publicats en revistes (Institut de Biomedicina (IBUB)) Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) |
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