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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:
It is part of: Molecules, 2015, vol. 20, num. 3, p. 4492-4515
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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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