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6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors

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Abstract

Dipeptidyl peptidase IV is a glycoprotein which removes N-terminal dipeptides from physiologically relevant polypeptides. An homologous series of 6-imino-2-thioxo-5-{[3,4,5-tris(methyloxy)phenyl]methyl}-2,5-dihydro-4(3H)-pyrimidinones has been tested for inhibition of DPP IV activity. The inhibitory effects at 0.1 mM were observed. Enzyme kinetic studies revealed that compounds inhibit DPP IV activity competitively. According to the molecular docking analysis, the inhibitors are anchored into the DPP IV hydrolytic site by interactions of the pyrimidinone core with Glu206, Tyr662, and Tyr547, with the alkyl chain entering the S1 pocket. We conclude that pyrimidinone-like compounds are a promising new scaffold for reversible inhibition of DPP IV.

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Abbreviations

DPP IV:

Dipeptidyl peptidase IV

GLP-1:

Glucagon-like peptide-1

GIP:

Glucose-dependent insulinotropic polypeptide

SAR:

Structure–activity relationship

RMSD:

Root mean square deviation

PDB:

Protein Data Bank

GOLD:

Genetic optimisation for ligand docking

MTS:

3-(4,5-Dimethylthiazole-2-yl)-5-(3-carboximethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazole

ECACC:

European Collection of Cell Cultures

THP-1:

Human monocytic leukemia

HepG2:

Human Caucasian hepatocyte carcinoma

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Acknowledgments

Special thanks to Professor Michael J. Parnham for his help in editing and critical reviewing of this manuscript, as well as to Dr. Andrew Leach for useful remarks. The authors are grateful to Snježana Dragojević for analytical characterization of the tested compounds. We also appreciate the excellent technical assistance provided by Ana Cvetković, Klara Markušić and Željka Tolić.

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Author notes

  1. Višnja Stepanić

    Present address: Department for Molecular Medicine, Ruđer Bošković Institute, P.O.B. 180, 10002, Zagreb, Croatia

  2. Donatella Verbanac

    Present address: University of Zagreb, School of Medicine, Center for Translational and Clinical Research, Šalata 2, 10000, Zagreb, Croatia

Authors and Affiliations

  1. GlaxoSmithKline Research Center Zagreb Ltd., Prilaz baruna Filipovića 29, 10000, Zagreb, Croatia

    Dubravko Jelić, Krunoslav Nujić, Višnja Stepanić, Krunoslav Kovačević & Donatella Verbanac

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  1. Dubravko Jelić
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  2. Krunoslav Nujić
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  3. Višnja Stepanić
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  4. Krunoslav Kovačević
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Correspondence to Dubravko Jelić.

Additional information

Dubravko Jelić and Donatella Verbanac equally contributed to this work.

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Jelić, D., Nujić, K., Stepanić, V. et al. 6-Imino-2-thioxo-pyrimidinones as a new class of dipeptidyl peptidase IV inhibitors. Med Chem Res 20, 339–345 (2011). https://doi.org/10.1007/s00044-010-9314-5

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  • DOI: https://doi.org/10.1007/s00044-010-9314-5

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