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

Article Details

Citation

Buchholz M, Heiser U, Schilling S, Niestroj AJ, Zunkel K, Demuth HU

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

J Med Chem. 2006 Jan 26;49(2):664-77.

PubMed ID
16420052 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
1-benzylimidazoleGlutaminyl-peptide cyclotransferaseKi (nM)7000830Details