Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design

Glutaminyl cyclase (QC) has been
implicated in the formation of
toxic amyloid plaques by generating the N-terminal
pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus
may participate in the pathogenesis of Alzheimer’s disease
(AD). We designed a library of glutamyl cyclase (QC) inhibitors based
on the proposed binding mode of the preferred substrate, Aβ3E−42. An in vitro structure–activity
relationship study identified several excellent QC inhibitors demonstrating
5- to 40-fold increases in potency compared to a known QC inhibitor.
When tested in mouse models of AD, compound 212 significantly
reduced the brain concentrations of pyroform Aβ and total Aβ
and restored cognitive functions. This potent Aβ-lowering effect
was achieved by incorporating an additional binding region into our
previously established pharmacophoric model, resulting in strong interactions
with the carboxylate group of Glu327 in the QC binding site. Our study
offers useful insights in designing novel QC inhibitors as a potential
treatment option for AD.