The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug-discovery approaches to develop potent, selective and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-% interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo, and is non-cytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
COBISS.SI-ID: 4444017
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, beta-secretase, beta-amyloid and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets beta inhibition of beta-secretase (IC50 hBACE-1 = 41.60 microM), inhibition of amyloid beta aggregation (IC50 Abeta = 3.09 microM), inhibition of tau aggregation (55% at 10 microM), as well as against symptomatic targets: butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 microM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
COBISS.SI-ID: 4465009
Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. Complexity of AD pathomechanism requires complex treatment e.g. multifunctional ligands targeting both causes and symptoms of the disease. Here, we present new multi-target-directed ligands combining pharmacophore fragments that provide blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta anti-aggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors (Ki = 18 nM) and non-competitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta anti-aggregation activity (IC50 = 1.27 microM) and ability to permeate through the blood-brain barrier. The presented findings may provide and excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
COBISS.SI-ID: 4470641