Development of matrix metalloproteinase-2 inhibitors for cardioprotection

Péter Bencsik, Krisztina Kupai, A. Görbe, Éva Kenyeres, Zoltán V. Varga, János Pálóczi, Renáta Gáspár, László Kovács, Lutz Weber, Ferenc Takács, István Hajdú, Gabriella Fabó, S. Cseh, László Barna, T. Csont, C. Csonka, György Dormán, Péter Ferdinandy

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number296
JournalFrontiers in Pharmacology
Volume9
Issue numberAPR
DOIs
Publication statusPublished - Apr 5 2018

Fingerprint

Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 2
Thiazoles
Matrix Metalloproteinases
Carboxylic Acids
Hydroxamic Acids
MMPI
Libraries
Myocardial Infarction
Gelatin
Cardiac Myocytes
Computer Simulation
Catalytic Domain
imidazole
Wounds and Injuries

Keywords

  • Cardioprotection
  • Heart
  • Ischemia/reperfusion injury
  • Lead candidate
  • Matrix metalloproteinase
  • MMP-2 inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Bencsik, P., Kupai, K., Görbe, A., Kenyeres, É., Varga, Z. V., Pálóczi, J., ... Ferdinandy, P. (2018). Development of matrix metalloproteinase-2 inhibitors for cardioprotection. Frontiers in Pharmacology, 9(APR), [296]. https://doi.org/10.3389/fphar.2018.00296

Development of matrix metalloproteinase-2 inhibitors for cardioprotection. / Bencsik, Péter; Kupai, Krisztina; Görbe, A.; Kenyeres, Éva; Varga, Zoltán V.; Pálóczi, János; Gáspár, Renáta; Kovács, László; Weber, Lutz; Takács, Ferenc; Hajdú, István; Fabó, Gabriella; Cseh, S.; Barna, László; Csont, T.; Csonka, C.; Dormán, György; Ferdinandy, Péter.

In: Frontiers in Pharmacology, Vol. 9, No. APR, 296, 05.04.2018.

Research output: Contribution to journalArticle

Bencsik, P, Kupai, K, Görbe, A, Kenyeres, É, Varga, ZV, Pálóczi, J, Gáspár, R, Kovács, L, Weber, L, Takács, F, Hajdú, I, Fabó, G, Cseh, S, Barna, L, Csont, T, Csonka, C, Dormán, G & Ferdinandy, P 2018, 'Development of matrix metalloproteinase-2 inhibitors for cardioprotection', Frontiers in Pharmacology, vol. 9, no. APR, 296. https://doi.org/10.3389/fphar.2018.00296
Bencsik, Péter ; Kupai, Krisztina ; Görbe, A. ; Kenyeres, Éva ; Varga, Zoltán V. ; Pálóczi, János ; Gáspár, Renáta ; Kovács, László ; Weber, Lutz ; Takács, Ferenc ; Hajdú, István ; Fabó, Gabriella ; Cseh, S. ; Barna, László ; Csont, T. ; Csonka, C. ; Dormán, György ; Ferdinandy, Péter. / Development of matrix metalloproteinase-2 inhibitors for cardioprotection. In: Frontiers in Pharmacology. 2018 ; Vol. 9, No. APR.
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