The most common variant of dementia is Alzheimer’s disease, a neurodegenerative disease characterized by aggregated amyloid β and hyperphosphorylated tau, which manifests as a progressive deterioration of cognitive functions. Before the approval of two monoclonal antibodies in the last two years, only symptomatic treatment, predominantly based on cholinesterase inhibitors, was available. Human butyrylcholinesterase (hBChE) is a validated drug target in several areas, such as neurodegenerative diseases, detoxification of xenobiotics, nerve agent protection, and ghrelin homeostasis.
In this doctoral thesis, we optimized a new structural class of indole-based, selective, reversible hBChE inhibitors. We noticed that an additional π–π interaction with Trp82 in choline-binding pocket could be gained by the introduction of an aromatic ring at the distal end of the cycloheptyl ring of these inhibitors, while the central α-aminoamide moiety could be replaced by a tertiary amine without a loss in inhibitory activity. Taking it one step further, we turned reversible inhibitors into pseudoirreversible covalent ones by introducing a carbamate warhead onto the indole ring. Carbamoylation of catalytic Ser198 was confirmed using different complementary techniques, and through optimization of steric and electronic properties of the carbamate N-substituents, the rate of reactivation could be prolonged or shortened.
Furthermore, by rational design, we have prepared multifunctional compounds that achieve both hBChE inhibition and antagonism at α2A adrenoreceptors, and could mean a disease-modifying treatment of Alzheimer's disease. More specifically, these are carbamate pleiotropic prodrugs of a α2A antagonist, atipamezole, that are metabolically activated by hBChE, which is itself inhibited during the process. The liberated atipamezole binds to the α2A adrenoreceptors and blocks the cascade that leads to tau hyperphosphorylation. For one lead compound, we demonstrated its per os availability, blood-brain barrier permeability, and improvement of cognitive functions in a mice model.
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