RT Journal Article
T1 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
A1 Codony, Sandra
A1 Pont, Caterina
A1 Griñán Ferré, Christian
A1 Pede-Mattatelli, Ania di
A1 Calvó Tusell, Carla
A1 Feixas, Ferrán
A1 Osuna, Sílvia
A1 Jarné Ferrer, Júlia
A1 Naldi, Marina
A1 Bartolini, Manuela
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Pérez, Belén
A1 Bartra, Clara
A1 Sanfeliu, Coral
A1 Juárez Jiménez, Jordi
A1 Morisseau, Christophe
A1 Hammock, Bruce D.
A1 Pallàs, Mercè
A1 Vázquez, Santiago
A1 Muñoz Torrero, Diego
K1 Inflammation
K1 Inhibition
K1 Inhibitors
K1 Peptides and proteins
K1 Rodent models
AB 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, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration
PB ACS Publications
YR 2022
FD 2022-03-10
LK https://hdl.handle.net/10347/45113
UL https://hdl.handle.net/10347/45113
LA eng
NO Sandra Codony, Caterina Pont, Christian Griñán-Ferré, Ania Di Pede-Mattatelli, Carla Calvó-Tusell, Ferran Feixas, Sílvia Osuna, Júlia Jarné-Ferrer, Marina Naldi, Manuela Bartolini, María Isabel Loza, José Brea, Belén Pérez, Clara Bartra, Coral Sanfeliu, Jordi Juárez-Jiménez, Christophe Morisseau, Bruce D. Hammock, Mercè Pallàs, Santiago Vázquez, and Diego Muñoz-Torrero Journal of Medicinal Chemistry 2022 65 (6), 4909-4925 DOI: 10.1021/acs.jmedchem.1c02150
NO This work was supported by grants PID2020-118127RB-I00, SAF2017-82771-R, PID2020-115683GA-I00, PGC2018-102192-B-I00, PID2019-106285RB, and RTI2018-101032-J-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, ED431C 2018/21 and ED431G 2019/02 from Xunta de Galicia, and 2017SGR106, 2017SGR1707, and 2019LLAV00017 from AGAUR. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Fellowships from Ministerio de Educación, Cultura y Deporte to C.P. (FPU15/01131), from the University of Barcelona to S.C., and a starting grant from the European Research Council (ERC-2015-StG-679001-NetMoDEzyme) to S.O. are gratefully acknowledged. We thank Ms. Cecilia Mariani for technical assistance in the assays with mAChE
DS Minerva
RD 27 abr 2026