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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
Jarné-Ferrer, Júlia
Naldi, Marina
Bartolini, Manuela
Loza, María Isabel
Brea, José
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.
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It is part of: Journal of Medicinal Chemistry, 2022, vol. 65, num. 6, p. 4909-4925
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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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