Multitarget Drug Discovery for Alzheimer's Disease: Triazinones as BACE‐1 and GSK‐3β Inhibitors

Abstract

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3β. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) μM and (14.67±0.78) μM for BACE-1 and GSK-3β, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…On these premises, we recently reported on a fragment-based program, which led to 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of dual-targeted compounds able to simultaneously modulate BACE-1 and glycogen synthase kinase-3 (GSK-3β) enzymes [51]. Thus, the new hybrid compounds were initially conceived of to exert a carefully-selected anti-AD MTDL profile: (i) ChE inhibition; (ii) Cu(II) and Zn(II) chelation; (iii) ROS scavenging; and (iv) Aβ anti-aggregating activity.…”

“…On these premises, we recently reported on a fragment-based program, which led to 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of dual-targeted compounds able to simultaneously modulate BACE-1 and glycogen synthase kinase-3 (GSK-3β) enzymes [51].…”

“…Particularly, we used a ligand-based approach to merge in a single pharmacophoric unit a guanidino motif and a cyclic amide group, as structural elements responsible for targeting BACE-1 and GSK-3β, respectively [51] (Figure 4).…”

“…Particularly, we used a ligand-based approach to merge in a single pharmacophoric unit a guanidino motif and a cyclic amide group, as structural elements responsible for targeting BACE-1 and GSK-3β, respectively [51] (Figure 4). The guanidino moiety, a key functionality of several BACE-1 inhibitors, such as acylguanidines and aminoimidazoles, may bind to the catalytic aspartic dyad of BACE-1 [52,53].…”

“…Among several others possible identified chemotypes, the 6-amino-4-phenyl triazinone core was selected as a suitable scaffold by means of molecular modelling studies [51].…”