Identification of N-phenyl-3-methoxy-4-pyridinones as orally bioavailable H3 receptor antagonists and β-amyloid aggregation inhibitors for the treatment of Alzheimer's disease

Based on our previous work, a series of N-phenyl-3-methoxy-4-pyridinone derivatives were designed as orally bioavailable dual functional agents for therapy of Alzheimer's disease, through introducing alkyloxy moiety into 4-pyridinone ring to avoid the possible phase II metabolism of 3-hydroxy-4-pyridinone in lead compound 3-hydroxy-2-methyl-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (4). In vitro studies indicated that most of these compounds exhibit excellent H-3 receptor antagonistic activities and potent self-induced A beta(1-40)/A beta(1-42) aggregation inhibitory activities. In particular, 3-methoxy-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (7i) demonstrated IC50 value of 0.52 nM in H3R antagonism and good selectivity over other histamine receptor subtypes. The transmission electron microscopy (TEM) images showed that compound 7i can inhibit self-mediated A beta(1-40)/A beta(1-42) aggregation efficiently. As expected, it exhibited desirable pharmacokinetic properties in plasma and good BBB permeability. Furthermore, compound 7i can efficiently block (R)-alpha-methylhistamine- induced dipsogenia and reverse scopolamine-induced learning deficits of rats. All above results indicated that compound 7i was a promising orally bioavailable dual functional agents with potential use in the treatment of Alzheimer's disease. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

The newly designed compounds showed excellent H-3 receptor antagonistic activities and potent self-induced A beta aggregation inhibitory activities in vitro experiments.