2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Mar 24;65(6):4909-4925. doi: 10.1021/acs.jmedchem.1c02150.
Sandra Codony 1,  Caterina Pont 1,  Christian Griñán-Ferré 2,  Ania Di Pede-Mattatelli 3,  Carla Calvó-Tusell 4,  Ferran Feixas 4,  Sílvia Osuna 4 5,  Júlia Jarné-Ferrer 2,  Marina Naldi 6,  Manuela Bartolini 6,  María Isabel Loza 7,  José Brea 7,  Belén Pérez 8,  Clara Bartra 9,  Coral Sanfeliu 9,  Jordi Juárez-Jiménez 3,  Christophe Morisseau 10,  Bruce D Hammock 10,  Mercè Pallàs 2,  Santiago Vázquez 1,  Diego Muñoz-Torrero 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona (UB), Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 2 Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Neurosciences, University of Barcelona (UB), Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 3 Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona (UB), Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 4 CompBioLab Group, Departament de Química and Institut de Química Computacional i Catàlisi (IQCC), Universitat de Girona, C/ Maria Aurèlia Capmany 69, E-17003 Girona, Spain.
  • 5 Institució Catalana de Recerca i Estudis Avançats (ICREA), E-08010 Barcelona, Spain.
  • 6 Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy.
  • 7 BioFarma Research Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Av. de Barcelona s/n, E-15782 Santiago de Compostela, Spain.
  • 8 Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Spain.
  • 9 Institute of Biomedical Research of Barcelona, CSIC and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló, 149, E-08036 Barcelona, Spain.
  • 10 Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, California 95616, United States.
PMID: 35271276 DOI: 10.1021/acs.jmedchem.1c02150
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.

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