title: Multigram synthesis and in vivo efficacy studies of a novel multitarget anti-Alzheimer's compound.
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.
authors.affiliation: 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. irenesola872@gmail.com.
authors.forename: Irene
authors.initials: I
authors.lastname: Sola
authors.affiliation: 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. elisabet.viayna@gmail.com.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Viayna
authors.affiliation: 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. tania.gomez.nadal@gmail.com.
authors.forename: Tània
authors.initials: T
authors.lastname: Gómez
authors.affiliation: 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. cargalcan@hotmail.com.
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.affiliation: 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. matteo.cassina01@universitadipavia.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassina
authors.affiliation: 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. camps@ub.edu.
authors.forename: Pelayo
authors.initials: P
authors.lastname: Camps
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, Italy. margherita.romeo@marionegri.it.
authors.forename: Margherita
authors.initials: M
authors.lastname: Romeo
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, Italy. luisa.diomede@marionegri.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, Italy. mario.salmona@marionegri.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Chiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, France. pfranco@chiral.fr.
authors.forename: Pilar
authors.initials: P
authors.lastname: Franco
authors.affiliation: Chiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, France. mschaeffer@chiral.fr.
authors.forename: Mireille
authors.initials: M
authors.lastname: Schaeffer
authors.affiliation: Chiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, France. dcolantuono@chiral.fr.
authors.forename: Diego
authors.initials: D
authors.lastname: Colantuono
authors.affiliation: Chiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, France. drobin@chiral.fr.
authors.forename: David
authors.initials: D
authors.lastname: Robin
authors.affiliation: Neuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, Austria. Daniela.Brunner@qps.com.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
authors.affiliation: Neuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, Austria. Nicole.Taub@qps.com.
authors.forename: Nicole
authors.initials: N
authors.lastname: Taub
authors.affiliation: Neuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, Austria. Birgit.Hutter-Paier@qps.com.
authors.forename: Birgit
authors.initials: B
authors.lastname: Hutter-Paier
authors.affiliation: 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. dmunoztorrero@ub.edu.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism*; D017173:Caenorhabditis elegans; D004195:Disease Models, Animal; D000077265:Donepezil; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
chemical_list: C545487:APP protein, human; C000603053:AVCRI104P4; D000634:Aminoquinolines; D016564:Amyloid beta-Protein Precursor; D006576:Heterocyclic Compounds, 4 or More Rings; D007189:Indans; D010880:Piperidines; C404519:huprine Y; D000077265:Donepezil