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
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
24 03 2022
24 03 2022
Historique:
pubmed:
11
3
2022
medline:
5
4
2022
entrez:
10
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35271276
doi: 10.1021/acs.jmedchem.1c02150
pmc: PMC8958510
doi:
Substances chimiques
Cholinesterase Inhibitors
0
Acetylcholinesterase
EC 3.1.1.7
Epoxide Hydrolases
EC 3.3.2.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4909-4925Subventions
Organisme : NIEHS NIH HHS
ID : P42 ES004699
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103616
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107767
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES030443
Pays : United States
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