Codony_2022_J.Med.Chem_65_4909

Reference

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 - Codony_2022_J.Med.Chem_65_4909
Author(s) : Codony S , Pont C , Grinan-Ferre C , Di Pede-Mattatelli A , Calvo-Tusell C , Feixas F , Osuna S , Jarne-Ferrer J , Naldi M , Bartolini M , Loza MI , Brea J , Perez B , Bartra C , Sanfeliu C , Juarez-Jimenez J , Morisseau C , Hammock BD , Pallas M , Vazquez S , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 65 :4909 , 2022
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.
ESTHER : Codony_2022_J.Med.Chem_65_4909
PubMedSearch : Codony_2022_J.Med.Chem_65_4909
PubMedID: 35271276

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Citations formats

Codony S, Pont C, Grinan-Ferre C, Di Pede-Mattatelli A, Calvo-Tusell C, Feixas F, Osuna S, Jarne-Ferrer J, Naldi M, Bartolini M, Loza MI, Brea J, Perez B, Bartra C, Sanfeliu C, Juarez-Jimenez J, Morisseau C, Hammock BD, Pallas M, Vazquez S, Munoz-Torrero D (2022)
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
Journal of Medicinal Chemistry 65 :4909

Codony S, Pont C, Grinan-Ferre C, Di Pede-Mattatelli A, Calvo-Tusell C, Feixas F, Osuna S, Jarne-Ferrer J, Naldi M, Bartolini M, Loza MI, Brea J, Perez B, Bartra C, Sanfeliu C, Juarez-Jimenez J, Morisseau C, Hammock BD, Pallas M, Vazquez S, Munoz-Torrero D (2022)
Journal of Medicinal Chemistry 65 :4909