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
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)–...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-03, Vol.65 (6), p.4909-4925 |
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| container_title | Journal of medicinal chemistry |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.1c02150 |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c02150</identifier><identifier>PMID: 35271276</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acetylcholinesterase ; Alzheimer Disease - drug therapy ; Animals ; Cholinesterase Inhibitors - pharmacology ; Cholinesterase Inhibitors - therapeutic use ; Disease Models, Animal ; Epoxide Hydrolases - antagonists & inhibitors ; Mice</subject><ispartof>Journal of medicinal chemistry, 2022-03, Vol.65 (6), p.4909-4925</ispartof><rights>2022 The Authors. Published by American Chemical Society</rights><rights>2022 The Authors. 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Med. Chem</addtitle><description>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. 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2022-03, Vol.65 (6), p.4909-4925 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8958510 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Acetylcholinesterase Alzheimer Disease - drug therapy Animals Cholinesterase Inhibitors - pharmacology Cholinesterase Inhibitors - therapeutic use Disease Models, Animal Epoxide Hydrolases - antagonists & inhibitors Mice |
| 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 |
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