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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 |
Author: | Codony Gisbert, Sandra Pont Masanet, Caterina Griñán Ferré, Christian Di Pede-Mattatelli, Ania Calvó-Tusell, Carla Feixas, Ferran Osuna, Sílvia Jarne Ferrer, Júlia Naldi, Marina Bartolini, Manuela Loza, María Isabel Brea, José Bartolini Pérez, Belén Bartra, Clara Sanfeliu i Pujol, Coral Juárez Jiménez, Jordi Morisseau, Christophe Hammock, Bruce D. Pallàs i Llibería, Mercè, 1964- Vázquez Cruz, Santiago Muñoz-Torrero López-Ibarra, Diego |
Keywords: | Desenvolupament de medicaments Malaltia d'Alzheimer Química farmacèutica Drug development Alzheimer's disease Pharmaceutical chemistry |
Issue Date: | 2022 |
Publisher: | American Chemical Society |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1021/acs.jmedchem.1c02150 |
It is part of: | Journal of Medicinal Chemistry, 2022, vol. 65, num. 6, p. 4909-4925 |
URI: | https://hdl.handle.net/2445/184725 |
Related resource: | https://doi.org/10.1021/acs.jmedchem.1c02150 |
ISSN: | 0022-2623 |
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 |
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