The First Potent Inhibitors for Human Glutaminyl Cyclase: Synthesis and Structure−Activity Relationship

The first effective inhibitors for human glutaminyl cyclase (QC) are described. The structures are developed
by applying a ligand-based optimization approach starting from imidazole. Screening of derivatives of that
heterocycle led to compounds of the imidazol-1-yl-alkyl thiourea type as a lead scaffold. A library of thiourea
derivatives was synthesized, resulting in an inhibitory improvement by 2 orders of magnitude, leading to
1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea as a potent inhibitor. Systematic exploitation
of the scaffold revealed a strong impact on the inhibitory efficacy and resulted in the development of
imidazole−propyl−thioamides as another new class of potent inhibitors. A flexible alignment of the most
potent compounds of the thioamide and thiourea class and a QC substrate revealed a good match of
characteristic features of the molecules, which suggests a similar binding mode of both inhibitors and the
substrate to the active site of QC.