%A Bencsik,Péter %A Kupai,Krisztina %A Görbe,Anikó %A Kenyeres,Éva %A Varga,Zoltán V. %A Pálóczi,János %A Gáspár,Renáta %A Kovács,László %A Weber,Lutz %A Takács,Ferenc %A Hajdú,István %A Fabó,Gabriella %A Cseh,Sándor %A Barna,László %A Csont,Tamás %A Csonka,Csaba %A Dormán,György %A Ferdinandy,Péter %D 2018 %J Frontiers in Pharmacology %C %F %G English %K matrix metalloproteinase,MMP-2 inhibitor,Heart,ischemia/reperfusion injury,Cardioprotection,lead candidate %Q %R 10.3389/fphar.2018.00296 %W %L %M %P %7 %8 2018-April-05 %9 Original Research %# %! Cardioprotection by MMP inhibition %* %< %T Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection %U https://www.frontiersin.org/articles/10.3389/fphar.2018.00296 %V 9 %0 JOURNAL ARTICLE %@ 1663-9812 %X 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.