1. Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy.
- Author
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Mezeiova E, Korabecny J, Sepsova V, Hrabinova M, Jost P, Muckova L, Kucera T, Dolezal R, Misik J, Spilovska K, Pham NL, Pokrievkova L, Roh J, Jun D, Soukup O, Kaping D, and Kuca K
- Subjects
- Acetylcholinesterase, Alzheimer Disease drug therapy, Aminoquinolines chemical synthesis, Binding Sites, Blood-Brain Barrier metabolism, Butyrylcholinesterase, Catalytic Domain, Cell Line, Tumor, Cell Survival drug effects, Cholinesterase Inhibitors chemistry, Cholinesterase Inhibitors pharmacology, Drug Design, Enzyme Activation drug effects, Heterocyclic Compounds, 4 or More Rings chemistry, Heterocyclic Compounds, 4 or More Rings pharmacology, Humans, Hydrolysis, Inhibitory Concentration 50, Models, Molecular, Molecular Conformation, Molecular Structure, Permeability, Protein Binding, Structure-Activity Relationship, Tacrine analogs & derivatives, Tacrine chemistry, Tacrine pharmacology, Aminoquinolines chemistry, Aminoquinolines pharmacology, Drug Discovery
- Abstract
Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
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