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

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    The First Potent Inhibitors for Human Glutaminyl Cyclase:  Synthesis and Structure−Activity Relationship
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    Departments of Medicinal Chemistry and Enzymology, Probiodrug AG, Weinbergweg 22, 06120 Halle, Germany
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2006, 49, 2, 664–677
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    https://doi.org/10.1021/jm050756e
    Published December 16, 2005
    Copyright © 2006 American Chemical Society
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    Abstract

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    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.

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     Department of Medicinal Chemistry.

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     Corresponding author. Tel:  +49 (0)345 5559908. Fax: +49 (0) 345 5559901. E-mail:  [email protected].

    ‡

     Department of Enzymology.

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    MS, HPLC, and NMR data and a zipped file containing a table with the solutions of the flexible alignment with the respective average strain energy (U) and configuration score (S) values in sdf format. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2006, 49, 2, 664–677
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    https://doi.org/10.1021/jm050756e
    Published December 16, 2005
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