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

摘要

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 l-(3-(1H-imidazol-l-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.