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.
Authors: Codony, Sandra; Pont, 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, Coral; Juárez-Jiménez, Jordi; Morisseau, Christophe; Hammock, Bruce D; Pallàs, Mercè; Vázquez, Santiago; Muñoz-Torrero, Diego
Published In J Med Chem, (2022 Mar 24)
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, 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.
PubMed ID:
35271276
MeSH Terms: Acetylcholinesterase*; Alzheimer Disease*/drug therapy; Animals; Cholinesterase Inhibitors/pharmacology; Cholinesterase Inhibitors/therapeutic use; Disease Models, Animal; Epoxide Hydrolases*/antagonists & inhibitors; Mice