Alzheimer's disease (AD) is defined as a progressive, irreversible neurodegenerative disorder manifested by a gradual decline in cognitive functions and associated behavioral and psychological disturbances. Among most common pathological alterations in the development of the disease are formation of extracellular insoluble aggregates of amyloid beta, intracellular neurofibrillary tangles, acetylcholine deficiency in the brain and oxidative stress. All these processes lead to neuronal death and consequently brain atrophy. Most affected are cholinergic neurons, therefore the development of therapeutics focused on compounds that ameliorate acetylcholine deficiency. Currently approved drugs only alleviate the symptoms of the disease and have little effect on the course of the disease. Registered drugs are acetylcholine esterase (AChE) inhibitors (rivastigmine, donepezil, galantamine) and NMDA receptor antagonist (memantine).
Recent studies showed that in the late stages of AD, the reduced AChE activity is compensated by structurally related enzyme - butyrylcholinesterase (BuChE). Consequently, BuChE inhibition is a promising therapeutic approach in the late stages of AD. Based on the structure of previously identified BuChE inhibitors, 15 analogues of 1-(2-piperidin-1-yl)ethyl)pyrrolidin-2-one were synthesized. Substituents on the position 3 of piperidine were altered in order to optimize the binding of compounds to the acyl binding pocket of BuChE active site. The synthesis was started from 3-carboxypiperidine, which was first protected as tert-butylcarbamate. 3-Carboxylate was transformed into Weinreb amide, which was selectively reduced into carbaldehylde. 3-Formylpiperidine was used as the main building block in Witting reaction to yield 3-vinyl and 3-phenethylpiperidines. Acid-catalysed deprotection of tert-butylcarbamate furnished secondary amine that was alkylated with N-(2-bromoethyl)pyrrolidin-2-one. Final compounds were assayed for the inhibition of BuChE and their selectivity over AChE using the Ellman’s method. The most potent inhibitor was compound 48. Derivatives 40–43, 46 in 47 also showed potent inhibition of hBuChE in comparison to lead compound C. Analogs selectively inhibited hBuChE in the nanomolar range, and thus represent a good starting point for further optimization.
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