Identification of N-phenyl-3-methoxy-4-pyridinones as orally bioavailable H 3 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 receptor antagonistic activities and potent self-induced Aβ /Aβ aggregation inhibitory activities. In particular, 3-methoxy-1-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-pyridin-4(1H)-one (7i) demonstrated IC value of 0.52 nM in H R antagonism and good selectivity over other histamine receptor subtypes. The transmission electron microscopy (TEM) images showed that compound 7i can inhibit self-mediated Aβ /Aβ aggregation efficiently. As expected, it exhibited desirable pharmacokinetic properties in plasma and good BBB permeability. Furthermore, compound 7i can efficiently block (R)-α-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.