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, Aβ. 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.
Alzheimer’s
disease (AD) is an incurable, progressive neurodegenerative
disease whose pathogenesis cannot be defined by one single element
but consists of various factors; thus, there is a call for alternative
approaches to tackle the multifaceted aspects of AD. Among the potential
alternative targets, we aim to focus on glutaminyl cyclase (QC), which
reduces the toxic pyroform of β-amyloid in the brains of AD
patients. On the basis of a putative active conformation of the prototype
inhibitor 1, a series of N-substituted thiourea, urea,
and α-substituted amide derivatives were developed. The structure–activity
relationship analyses indicated that conformationally restrained inhibitors
demonstrated much improved QC inhibition in vitro compared to nonrestricted
analogues, and several selected compounds demonstrated desirable therapeutic
activity in an AD mouse model. The conformational analysis of a representative
inhibitor indicated that the inhibitor appeared to maintain the Z–E
conformation at the active site, as it is critical for its potent
activity.
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