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http://hdl.handle.net/2445/184725
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DC Field | Value | Language |
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dc.contributor.author | Codony Gisbert, Sandra | - |
dc.contributor.author | Pont Masanet, Caterina | - |
dc.contributor.author | Griñán Ferré, Christian | - |
dc.contributor.author | Di Pede-Mattatelli, Ania | - |
dc.contributor.author | Calvó-Tusell, Carla | - |
dc.contributor.author | Feixas, Ferran | - |
dc.contributor.author | Osuna, Sílvia | - |
dc.contributor.author | Jarné-Ferrer, Júlia | - |
dc.contributor.author | Naldi, Marina | - |
dc.contributor.author | Bartolini, Manuela | - |
dc.contributor.author | Loza, María Isabel | - |
dc.contributor.author | Brea, José | - |
dc.contributor.author | Bartolini | - |
dc.contributor.author | Pérez, Belén | - |
dc.contributor.author | Bartra, Clara | - |
dc.contributor.author | Sanfeliu i Pujol, Coral | - |
dc.contributor.author | Juárez Jiménez, Jordi | - |
dc.contributor.author | Morisseau, Christophe | - |
dc.contributor.author | Hammock, Bruce D. | - |
dc.contributor.author | Pallàs i Llibería, Mercè, 1964- | - |
dc.contributor.author | Vázquez Cruz, Santiago | - |
dc.contributor.author | Muñoz-Torrero López-Ibarra, Diego | - |
dc.date.accessioned | 2022-04-07T08:03:30Z | - |
dc.date.available | 2022-04-07T08:03:30Z | - |
dc.date.issued | 2022 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.uri | http://hdl.handle.net/2445/184725 | - |
dc.description.abstract | With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)‒TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, and human microsomal stability and lack of neurotoxicity, and rescued memory, synaptic plasticity and neuroinflammation in an AD mouse model, after low dose chronic oral administration. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Chemical Society | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1021/acs.jmedchem.1c02150 | - |
dc.relation.ispartof | Journal of Medicinal Chemistry, 2022, vol. 65, num. 6, p. 4909-4925 | - |
dc.relation.uri | https://doi.org/10.1021/acs.jmedchem.1c02150 | - |
dc.rights | cc by (c) Sandra Codony Gisbert, et al., 2022 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) | - |
dc.subject.classification | Desenvolupament de medicaments | - |
dc.subject.classification | Malaltia d'Alzheimer | - |
dc.subject.classification | Química farmacèutica | - |
dc.subject.other | Drug development | - |
dc.subject.other | Alzheimer's disease | - |
dc.subject.other | Pharmaceutical chemistry | - |
dc.title | Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 722346 | - |
dc.date.updated | 2022-04-07T08:03:30Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/679001/EU//NetMoDEzyme | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Publicacions de projectes de recerca finançats per la UE |
Files in This Item:
File | Description | Size | Format | |
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722346.pdf | 6.02 MB | Adobe PDF | View/Open |
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