Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound
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 chro...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2015-03-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/20/3/4492 |
| _version_ | 1818317549377421312 |
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| author | Irene Sola Elisabet Viayna Tània Gómez Carles Galdeano Matteo Cassina Pelayo Camps Margherita Romeo Luisa Diomede Mario Salmona Pilar Franco Mireille Schaeffer Diego Colantuono David Robin Daniela Brunner Nicole Taub Birgit Hutter-Paier Diego Muñoz-Torrero |
| author_facet | Irene Sola Elisabet Viayna Tània Gómez Carles Galdeano Matteo Cassina Pelayo Camps Margherita Romeo Luisa Diomede Mario Salmona Pilar Franco Mireille Schaeffer Diego Colantuono David Robin Daniela Brunner Nicole Taub Birgit Hutter-Paier Diego Muñoz-Torrero |
| author_sort | Irene Sola |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T09:39:05Z |
| format | Article |
| id | doaj.art-07c01f55a50348b5a7e8cec7faab37ec |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-13T09:39:05Z |
| publishDate | 2015-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-07c01f55a50348b5a7e8cec7faab37ec2022-12-21T23:52:14ZengMDPI AGMolecules1420-30492015-03-012034492451510.3390/molecules20034492molecules20034492Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s CompoundIrene Sola0Elisabet Viayna1Tània Gómez2Carles Galdeano3Matteo Cassina4Pelayo Camps5Margherita Romeo6Luisa Diomede7Mario Salmona8Pilar Franco9Mireille Schaeffer10Diego Colantuono11David Robin12Daniela Brunner13Nicole Taub14Birgit Hutter-Paier15Diego Muñoz-Torrero16Laboratori 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, SpainLaboratori 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, SpainLaboratori 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, SpainLaboratori 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, SpainLaboratori 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, SpainLaboratori 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, SpainDepartment of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, ItalyDepartment of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, ItalyDepartment of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, Milan 20156, ItalyChiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, FranceChiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, FranceChiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, FranceChiral Technologies Europe, Parc d'Innovation, Bd. Gonthier d'Andernach, Illkirch F-67400, FranceNeuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, AustriaNeuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, AustriaNeuropharmacology Department of QPS Austria-Gmbh, Parkring 12, Grambach 8074, AustriaLaboratori 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, SpainWe 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.http://www.mdpi.com/1420-3049/20/3/4492disease-modifying anti-Alzheimer drugsmultitarget drugsneuroprotectionanimal models of Alzheimer’s diseasemultigram preparative chromatographic resolution |
| spellingShingle | Irene Sola Elisabet Viayna Tània Gómez Carles Galdeano Matteo Cassina Pelayo Camps Margherita Romeo Luisa Diomede Mario Salmona Pilar Franco Mireille Schaeffer Diego Colantuono David Robin Daniela Brunner Nicole Taub Birgit Hutter-Paier Diego Muñoz-Torrero Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound Molecules disease-modifying anti-Alzheimer drugs multitarget drugs neuroprotection animal models of Alzheimer’s disease multigram preparative chromatographic resolution |
| title | Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound |
| title_full | Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound |
| title_fullStr | Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound |
| title_full_unstemmed | Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound |
| title_short | Multigram Synthesis and in Vivo Efficacy Studies of a Novel Multitarget Anti-Alzheimer’s Compound |
| title_sort | multigram synthesis and in vivo efficacy studies of a novel multitarget anti alzheimer s compound |
| topic | disease-modifying anti-Alzheimer drugs multitarget drugs neuroprotection animal models of Alzheimer’s disease multigram preparative chromatographic resolution |
| url | http://www.mdpi.com/1420-3049/20/3/4492 |
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