Medicinal Chemistry Research

, Volume 20, Issue 3, pp 339–345 | Cite as

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

  • Dubravko Jelić
  • Krunoslav Nujić
  • Višnja Stepanić
  • Krunoslav Kovačević
  • Donatella Verbanac
Original Research
  • 88 Downloads

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.

Keywords

DPP IV inhibitor Pyrimidinone Enzyme kinetics Molecular docking Cytotoxicity 

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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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Dubravko Jelić
    • 1
  • Krunoslav Nujić
    • 1
  • Višnja Stepanić
    • 1
    • 2
  • Krunoslav Kovačević
    • 1
  • Donatella Verbanac
    • 1
    • 3
  1. 1.GlaxoSmithKline Research Center Zagreb Ltd.ZagrebCroatia
  2. 2.Department for Molecular MedicineRuđer Bošković InstituteZagrebCroatia
  3. 3.University of Zagreb, School of Medicine, Center for Translational and Clinical ResearchZagrebCroatia

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