| Title : Dual GSK-3beta\/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery - Jiang_2018_ACS.Med.Chem.Lett_9_171 |
| Author(s) : Jiang XY , Chen TK , Zhou JT , He SY , Yang HY , Chen Y , Qu W , Feng F , Sun HP |
| Ref : ACS Med Chem Lett , 9 :171 , 2018 |
|
Abstract :
Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3beta (GSK-3beta) and human acetylcholinesterase (hAChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3beta/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both hAChE (IC50 = 6.5 nM) and hGSK-3beta kinase activity (IC50 = 66 nM). It also showed good inhibitory effect on beta-amyloid self-aggregation (inhibitory rate = 46%) at 20 muM. Western blot analysis revealed that compound 2f inhibited hyperphosphorylation of tau protein in mouse neuroblastoma N2a-Tau cells. In vivo studies confirmed that 2f significantly ameliorated the cognitive disorders in scopolamine-treated ICR mice and less hepatotoxicity than tacrine. This study provides new leads for assessment of GSK-3beta and AChE pathway dual inhibition as a promising strategy for AD treatment. |
| PubMedSearch : Jiang_2018_ACS.Med.Chem.Lett_9_171 |
| PubMedID: 29541355 |
| Inhibitor | CHEMBL4278686 |
Jiang XY, Chen TK, Zhou JT, He SY, Yang HY, Chen Y, Qu W, Feng F, Sun HP (2018)
Dual GSK-3beta\/AChE Inhibitors as a New Strategy for Multitargeting Anti-Alzheimer's Disease Drug Discovery
ACS Med Chem Lett
9 :171
Jiang XY, Chen TK, Zhou JT, He SY, Yang HY, Chen Y, Qu W, Feng F, Sun HP (2018)
ACS Med Chem Lett
9 :171