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.

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.

• Authors: 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, Diego Muñoz-Torrero
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 6 Pg. 4909-4925 (03 24 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35271276 (Publication Type: Journal Article)

Chemical References

• Cholinesterase Inhibitors
• Acetylcholinesterase
• Epoxide Hydrolases

Topics

• Acetylcholinesterase
• Alzheimer Disease (drug therapy)
• Animals
• Cholinesterase Inhibitors (pharmacology, therapeutic use)
• Disease Models, Animal
• Epoxide Hydrolases (antagonists & inhibitors)
• Mice