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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Mar 10

PMID 35271276

Authors

Sandra Codony

Caterina Pont

Christian Grinan-Ferre

Ania Di Pede-Mattatelli

Carla Calvo-Tusell

Ferran Feixas

Silvia Osuna

Julia Jarne-Ferrer

Marina Naldi

Manuela Bartolini

Maria Isabel Loza

Jose Brea

Belen Perez

Clara Bartra

Coral Sanfeliu

Jordi Juarez-Jimenez

Christophe Morisseau

Bruce D Hammock

Merce Pallas

Santiago Vazquez

Diego Munoz-Torrero

Affiliations

Soon will be listed here.

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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References

Morley J, Armbrecht H, Farr S, Kumar V . The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer's disease. Biochim Biophys Acta. 2011; 1822(5):650-6. DOI: 10.1016/j.bbadis.2011.11.015. View

Perez-Areales F, Turcu A, Barniol-Xicota M, Pont C, Pivetta D, Espargaro A . A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors. Eur J Med Chem. 2019; 180:613-626. DOI: 10.1016/j.ejmech.2019.07.051. View

Morisseau C, Hammock B . Measurement of soluble epoxide hydrolase (sEH) activity. Curr Protoc Toxicol. 2012; Chapter 4:Unit 4.23. DOI: 10.1002/0471140856.tx0423s33. View

Pont C, Ginex T, Grinan-Ferre C, Scheiner M, Mattellone A, Martinez N . From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects. Eur J Med Chem. 2021; 225:113779. DOI: 10.1016/j.ejmech.2021.113779. View

Bachurin S, Bovina E, Ustyugov A . Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends. Med Res Rev. 2017; 37(5):1186-1225. DOI: 10.1002/med.21434. View

Sun C, Zhang X, Morisseau C, Hwang S, Zhang Z, Hammock B . Discovery of Soluble Epoxide Hydrolase Inhibitors from Chemical Synthesis and Natural Products. J Med Chem. 2020; 64(1):184-215. PMC: 7942193. DOI: 10.1021/acs.jmedchem.0c01507. View

Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Volpini R, Amenta F . Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology. 2020; 190:108352. DOI: 10.1016/j.neuropharm.2020.108352. View

Nunes-Tavares N, Nery da Matta A, Batista e Silva C, Araujo G, Louro S, Hasson-Voloch A . Inhibition of acetylcholinesterase from Electrophorus electricus (L.) by tricyclic antidepressants. Int J Biochem Cell Biol. 2002; 34(9):1071-9. DOI: 10.1016/s1357-2725(02)00027-4. View

Taylor P, Lappi S . Interaction of fluorescence probes with acetylcholinesterase. The site and specificity of propidium binding. Biochemistry. 1975; 14(9):1989-97. DOI: 10.1021/bi00680a029. View

10.

Morisseau C, Hammock B . Epoxide hydrolases: mechanisms, inhibitor designs, and biological roles. Annu Rev Pharmacol Toxicol. 2005; 45:311-33. DOI: 10.1146/annurev.pharmtox.45.120403.095920. View

11.

Imig J . Eicosanoid blood vessel regulation in physiological and pathological states. Clin Sci (Lond). 2020; 134(20):2707-2727. DOI: 10.1042/CS20191209. View

12.

Ismaili L, Monnin J, Etievant A, Arribas R, Viejo L, Refouvelet B . (±)-: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease. ACS Chem Neurosci. 2021; 12(8):1328-1342. DOI: 10.1021/acschemneuro.0c00803. View

13.

Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J . Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease. J Med Chem. 2021; 64(11):7483-7506. DOI: 10.1021/acs.jmedchem.1c00160. View

14.

Ghosh A, Comerota M, Wan D, Chen F, Propson N, Hwang S . An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease. Sci Transl Med. 2020; 12(573). PMC: 7784555. DOI: 10.1126/scitranslmed.abb1206. View

15.

Lee K, Liu J, Wagner K, Pakhomova S, Dong H, Morisseau C . Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy. J Med Chem. 2014; 57(16):7016-30. PMC: 4148150. DOI: 10.1021/jm500694p. View

16.

Ruiz-Carmona S, Alvarez-Garcia D, Foloppe N, Garmendia-Doval A, Juhos S, Schmidtke P . rDock: a fast, versatile and open source program for docking ligands to proteins and nucleic acids. PLoS Comput Biol. 2014; 10(4):e1003571. PMC: 3983074. DOI: 10.1371/journal.pcbi.1003571. View

17.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

18.

Silman I, Sussman J . Acetylcholinesterase: how is structure related to function?. Chem Biol Interact. 2008; 175(1-3):3-10. DOI: 10.1016/j.cbi.2008.05.035. View

19.

Camps P, El Achab R , Morral J, Munoz-Torrero D, Badia A, Banos J . New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. J Med Chem. 2000; 43(24):4657-66. DOI: 10.1021/jm000980y. View

20.

Fu W, Wang X, Ip N . Targeting Neuroinflammation as a Therapeutic Strategy for Alzheimer's Disease: Mechanisms, Drug Candidates, and New Opportunities. ACS Chem Neurosci. 2018; 10(2):872-879. DOI: 10.1021/acschemneuro.8b00402. View