20.500.12556/RUL-179131 Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer’s disease The inherent complexity of Alzheimer’s disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood–brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α2-adrenergic antagonists–butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD. pleiotropic prodrug Alzheimer’s disease butyrylcholinesterase α2A adrenoreceptor disease-modifying treatment N-heterocyclic ureas carbamates neurodegenerative diseases true false true Angleški jezik Angleški jezik Članek v reviji 2026-02-06 04:52:34 2026-02-06 09:54:46 2026-02-07 05:00:01 0000-00-00 00:00:00 2025 0 0 Str. 4807-4828 no. 9 Vol. 15 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 615:616.89 2211-3843 10.1016/j.apsb.2025.07.005 249943299 Pleiotropic-Meden.pdf Pleiotropic-Meden.pdf 1 AE2B241DFF25600E4D85BD222C55D354 452a7454c6f8a7eb20ba858dd00c1e66e5aad7d2063f90804c1f1abd0fff3452 a9f1ac13-0339-11f1-a1ba-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=227388 https://www.sciencedirect.com/science/article/pii/S2211383525004605 1 32537538-030f-11f1-a1ba-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=227342 Fakulteta za farmacijo Veterinarska fakulteta 0 0 0