The first potent inhibitors for human glutaminyl cyclase: Synthesis and structure-activity relationship

被引:87
作者
Buchholz, M
Heiser, U [1 ]
Schilling, S
Niestroj, AJ
Zunkel, K
Demuth, HU
机构
[1] Probiodrug AG, Dept Med Chem, D-06120 Halle, Germany
[2] Probiodrug AG, Dept Enzymol, D-06120 Halle, Germany
关键词
D O I
10.1021/jm050756e
中图分类号
R914 [药物化学];
学科分类号
100701 ;
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 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.
引用
收藏
页码:664 / 677
页数:14
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