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Molecules 2015, 20(3), 4492-4515; doi:10.3390/molecules20034492

Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound

1
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, Barcelona E-08028, Spain
2
Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, Italy
3
Chiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, France
4
Neuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, Austria
*
Author to whom correspondence should be addressed.
Academic Editor: Jean Jacques Vanden Eynde
Received: 22 January 2015 / Revised: 25 February 2015 / Accepted: 3 March 2015 / Published: 10 March 2015
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: disease-modifying anti-Alzheimer drugs; multitarget drugs; neuroprotection; animal models of Alzheimer’s disease; multigram preparative chromatographic resolution disease-modifying anti-Alzheimer drugs; multitarget drugs; neuroprotection; animal models of Alzheimer’s disease; multigram preparative chromatographic resolution
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Sola, I.; Viayna, E.; Gómez, T.; Galdeano, C.; Cassina, M.; Camps, P.; Romeo, M.; Diomede, L.; Salmona, M.; Franco, P.; Schaeffer, M.; Colantuono, D.; Robin, D.; Brunner, D.; Taub, N.; Hutter-Paier, B.; Muñoz-Torrero, D. Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound. Molecules 2015, 20, 4492-4515.

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