Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3β inhibitors for Alzheimer’s disease

Discovery of Novel Tacrine–Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer’s Disease

“…Compared with 14a, key intermediates 14b and 14c were synthesized from starting materials 11b and 11c similarly. 38,40 Then, 14b and 14c were treated with corresponding intermediates from 18a−18m in the presence of K 2 CO 3 to yield target compounds 22a−22j (series 2).…”

“…Second, the pyrimidone moiety of the novel scaffold of hybrids was investigated mainly for potential GSK-3β inhibition. It was found that the introduction of a fluorine atom or the change of pyridine by a pyrimidine ring linked to the pyrimidone moiety would be beneficial for binding with GSK-3β; ,, therefore, compounds 14a – 14c were synthesized as described in Scheme . Compared with 14a , key intermediates 14b and 14c were synthesized from starting materials 11b and 11c similarly. , Then, 14b and 14c were treated with corresponding intermediates from 18a – 18m in the presence of K 2 CO 3 to yield target compounds 22a – 22j (series 2).…”

“…It was found that the introduction of a fluorine atom or the change of pyridine by a pyrimidine ring linked to the pyrimidone moiety would be beneficial for binding with GSK-3β; ,, therefore, compounds 14a – 14c were synthesized as described in Scheme . Compared with 14a , key intermediates 14b and 14c were synthesized from starting materials 11b and 11c similarly. , Then, 14b and 14c were treated with corresponding intermediates from 18a – 18m in the presence of K 2 CO 3 to yield target compounds 22a – 22j (series 2).…”

“…For key intermediates shown in Schemes and , compounds 14a , 14b , and 14c were successfully synthesized according to Uehara et al’s work (compound 28 ) and Fukunaga et al’s work (compound 6 and compound 26 ), respectively. Also, analogues 18a – 18m , 19a – 19e , 24a – 24e , and 25a – 25e , which are different tacrine derivatives bearing respective alkylamine, were smoothly synthesized according to Sun et al’s work using the similar method .…”

Combining in vitro and in silico Approaches to Find New Candidate Drugs Targeting the Pathological Proteins Related to the Alzheimer's Disease

“…Oral administration of the novel 2-(alkymorpholin-4-yl)-6- (3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones inhibited tau phosphorylation in mice. Molecular docking studies found that this compound has a higher affinity than the prototype drug UDA-680 [92]. The potential tau therapeutic strategies primarily include kinase inhibitors and phosphastase activators, immunotherapies, small molecular inhibitors of protein aggregation, and microtubule-stabilizing agents.…”