Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

  • Front Pharmacol. 2018 Apr 5;9:296. doi: 10.3389/fphar.2018.00296.
Péter Bencsik  1  2 ,  Krisztina Kupai  3 ,  Anikó Görbe  1  2 ,  Éva Kenyeres  1  2 ,  Zoltán V Varga  4 ,  János Pálóczi  4 ,  Renáta Gáspár  3 ,  László Kovács  5 ,  Lutz Weber  6 ,  Ferenc Takács  5 ,  István Hajdú  7  8 ,  Gabriella Fabó  7 ,  Sándor Cseh  7 ,  László Barna  8  9 ,  Tamás Csont  3 ,  Csaba Csonka  3 ,  György Dormán  7 ,  Péter Ferdinandy  2  4
Affiliations
  • 1. Cardiovascular Research Group, Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
  • 2. Pharmahungary Group, Szeged, Hungary.
  • 3. Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged, Hungary.
  • 4. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
  • 5. Infarmatik, Budapest, Hungary.
  • 6. OntoChem GmbH, Halle (Saale), Germany.
  • 7. Targetex Biosciences, Dunakeszi, Hungary.
  • 8. Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary.
  • 9. Microscopy Center at IEM HAS, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
PMID: 29674965 DOI: 10.3389/fphar.2018.00296
Abstract

The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 Inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 Inhibitor lead candidate for the treatment of acute myocardial infarction.

Keywords
MMP-2 inhibitor; cardioprotection; heart; ischemia/reperfusion injury; lead candidate; matrix metalloproteinase.
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