Reduced cholinergic transmission has an important role in Alzheimer's disease. Along with other neurodegenerative diseases, this most common form of dementia has an ever increasing incidence among the aging population. Butyrylcholinesterase becomes the main brain cholinesterase during disease progression, which makes it a promising druggable target in the development of new drugs for symptomatic treatment of Alzheimer's disease. Butyrylcholinesterase is less substrate-specific compared to acetylcholinesterase (it catalyzes hydrolysis of different esters, including butyryl- and succinylcholine) due to larger active site, which enables development of selective inhibitors.
Starting from a known selective tryptophan-based butyrylcholinesterase inhibitor, 34 analogues were prepared using time-tested peptide chemistry reactions (protection, amidation, deprotection), with two new heterocyclic tryptophan analogues prepared via Negishi reaction and four ?-aminoamides additionally modified.
The synthesized compounds exhibit high selectivity for butyrylcholinesterase, almost all are nanomolar inhibitors (the best inhibitor in the series, 34, has IC50 of 3,0 nM) with appropriate physicochemical properties, they are easy to synthesize, and offer additional options for further optimization as lead compound in the search for new drugs for symptomatic treatment of Alzheimer's disease.
The results of this master's thesis were published as part of an article in Chemical Communications (Meden, A et al. Tryptophan-Derived Butyrylcholinesterase Inhibitors as Promising Leads against Alzheimer’s Disease. Chem. Commun. 2019, 55 (26), 3765–3768. https://doi.org/10.1039/C9CC01330J).