Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease

作者：Wieckowska Anna^*; Wichur Tomasz; Godyn Justyna; Bucki Adam; Marcinkowska Monika; Siwek Agata; Wieckowski Krzysztof; Zareba Paula; Knez Damijan; Gluch-Lutwin Monika; Kazek Grzegorz; Latacz Gniewomir; Mika Kamil; Kolaczkowski Marcin; Korabecny Jan; Soukup Ondrej; Benkova Marketa; Kiec-Kononowicz Katarzyna; Gobec Stanislav; Malawska Barbara

来源：ACS Chemical Neuroscience, 2018, 9(5): 1195-1214.

DOI：10.1021/acschemneuro.8b00024

• Alzheimer's disease
• multitarget-directed ligands
• acetylcholinesterase inhibitors
• butyrylcholinesterase inhibitors
• 5-HT6 receptor antagonists
• inhibition of beta-amyloid aggregation

Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT(6 )receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT(6 )receptors (K-i= 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 mu M) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.