Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer’s Disease

High
expression of glutaminyl cyclase (QC) contributes to the initiation
of Alzheimer’s disease (AD) by catalyzing the generation of
neurotoxic pyroglutamate (pE)-modified β-amyloid (Aβ)
peptides. Preventing the generation of pE-Aβs by QC inhibition
has been suggested as a novel approach to a disease-modifying therapy
for AD. In this work, a series of diphenyl conjugated imidazole derivatives
(DPCIs) was rationally designed and synthesized. Analogues with this
scaffold exhibited potent inhibitory activity against human QC (hQC)
and good in vitro blood–brain barrier (BBB)
permeability. Further assessments corroborated that the selected hQC
inhibitor 28 inhibits the activity of hQC, dramatically
reduces the generation of pE-Aβs in cultured cells and in vivo, and improves the behavior of AD mice.