Structure–Activity Relationships of Benzimidazole-Based Glutaminyl Cyclase Inhibitors Featuring a Heteroaryl Scaffold

Glutaminyl cyclase (hQC) has emerged
as a new potential target
for the treatment of Alzheimer’s disease (AD). The inhibition
of hQC prevents of the formation of the Aβ3(pE)‑40,42 species which were shown to be of elevated neurotoxicity and are
likely to act as a seeding core, leading to an accelerated formation
of Aβ-oligomers and fibrils. This work presents a new class
of inhibitors of hQC, resulting from a pharmacophore-based screen.
Hit molecules were identified, containing benzimidazole as the metal
binding group connected to 1,3,4-oxadiazole as the central scaffold.
The subsequent optimization resulted in benzimidazolyl-1,3,4-thiadiazoles
and -1,2,3-triazoles with an inhibitory potency in the nanomolar range.
Further investigation into the potential binding mode of the new compound
classes combined molecular docking and site directed mutagenesis studies.