With an aging population, Alzheimer’s disease (AD) — the most common neurodegenerative disorder and form of dementia — increasingly challenges patients, families, and healthcare systems. Butyrylcholinesterase (BChE) plays a key role in the progressive decline of cholinergic transmission observed in AD. Mitogen-activated protein kinase p38α (p38α MAPK), on the other hand is emerging as a validated target in neurodegeneration, tau hyperphosphorylation, and amyloid plaque pathology.
In this doctoral dissertation, we computationally designed, synthesized, and evaluated first-in-class dual inhibitors of hBChE/p38α MAPK as potential anti-AD drugs. Replacing the phenoxy group of the hit compound with a benzyl group enabled π-π stacking with Trp430 of the BChE choline-binding pocket and favourable binding within p38α MAPK’s hydrophobic region I, achieving nanomolar inhibitory potencies on both targets. The two lead compounds showed selectivity for p38α MAPK in a panel of 103 kinases and were effective in vivo in two models of cognitive decline.
Subsequently, using rational design based on the crystal structures of the complexes of these compounds with the target enzymes, we developed carbamate-based pleiotropic prodrugs of p38α MAPK inhibitors. These prodrugs are activated via pseudo-irreversible covalent binding to Ser198 of BChE, releasing an alcohol that competitively inhibits p38α MAPK.
To enhance the affinity for p38α MAPK while retaining high selectivity over other kinases, we designed another series of dual carbamate inhibitors that covalently bind to BChE and act as allosteric p38α MAPK inhibitors. Introduction of the carbamate group produced compounds with low nanomolar affinity for BChE and procognitive effects in vivo, but also caused a loss of important interactions in the allosteric site of p38α MAPK and thus insufficient inhibitory potency for kinase selectivity evaluation.
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