Yao_2021_J.Med.Chem__

Reference

Title : Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease - Yao_2021_J.Med.Chem__
Author(s) : Yao H , Uras G , Zhang P , Xu S , Yin Y , Liu J , Qin S , Li X , Allen S , Bai R , Gong Q , Zhang H , Zhu Z , Xu J
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC(50) = 51.1 nM; GSK-3beta: IC(50) = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
ESTHER : Yao_2021_J.Med.Chem__
PubMedSearch : Yao_2021_J.Med.Chem__
PubMedID: 34024109

Related information

Inhibitor ACHE-GSK-3-27g

Citations formats

Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J, Qin S, Li X, Allen S, Bai R, Gong Q, Zhang H, Zhu Z, Xu J (2021)
Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
Journal of Medicinal Chemistry :

Yao H, Uras G, Zhang P, Xu S, Yin Y, Liu J, Qin S, Li X, Allen S, Bai R, Gong Q, Zhang H, Zhu Z, Xu J (2021)
Journal of Medicinal Chemistry :

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    [paper] => Yao_2021_J.Med.Chem__
    [author] => Yao H || Uras G || Zhang P || Xu S || Yin Y || Liu J || Qin S || Li X || Allen S || Bai R || Gong Q || Zhang H || Zhu Z || Xu J
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    [title] => Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE\/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
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            [content] => Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC(50) = 51.1 nM; GSK-3beta: IC(50) = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
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