Alzheimer`s disease (AD) is a chronic neurodegenerative irreversible progressive disease that represents about 70 % of all forms of dementias. Dementia is characterized by a group of symptoms such as cognitive dysfunction and is most common in elderly people.
The pathogenesis of AD is quite complex. During the past decades many hypotesis have been established. The most common and the oldest one is the cholinergic hypothesis, which highlights the deficiency in levels of neurotransmitter acetylcholine. In line with cholinergic hypothesis, others were also put forward: amyloid cascade hypothesis, tau hypothesis, mitochondrial cascade hypothesis and metal ion hypothesis.
The management of AD involves pharmacological treatment, including cognition-enhancing agents. Currently, available drugs are predominantly acetylcholinesterase inhibitors (AChE). However, the efficency of these drugs is limited, because they are not able to stop the neurodegeneration. Beside AChE there is also butyrylcolinesterase (BChE), the activity of which increases with the progression of AD. BChE is thus a promising drug target in advanced AD.
Software for ligand-based virtual screening LiSiCA was used to identifly new chemotype of BChE inhibitors. In the course of the master`s thesis we optimized this structure by varying the substituents on the phenyl ring. Starting nipecotic acid was transformed into aldehyde via Weinreb amide. The aldehyde was reacted in Witting reaction to obtain corresponding styrylpiperidines, which were further Boc-deprotected and alcylated with 1-(2bromoethyl)pyrrolidin-2-one to furnish final compounds. The synthesized compounds were biochemically evaluated on isolated recombinant human BChE using the method of Ellman.
Of all the synthesized compounds, compound 34 was the most effective BChE inhibitor (IC50 of 36 nM). The synthesized compounds were all high selective for BChE in comparison to AchE, with at least one to three log units better inhibitory potencies for the former.
|
