Show simple item record Bencsik, Péter Kupai, Krisztina Görbe, Anikó Kenyeres, Éva Varga, Zoltán Pálóczi, János Gáspár, Renáta Kovács László Lutz Weber Takács Ferenc Hajdú, István Fabó Gabriella Cseh, Sándor Barna, László Csont, Tamás Csonka, Csaba Dormán, György Ferdinandy, Péter 2018-06-05T07:29:55Z 2018-06-05T07:29:55Z 2018
dc.identifier 85045020075
dc.identifier.citation pagination=296, 14 pages; journalVolume=9; journalTitle=FRONTIERS IN PHARMACOLOGY;
dc.identifier.uri doi:10.3389/fphar.2018.00296
dc.description.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.
dc.relation.ispartof urn:issn:1663-9812
dc.title Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection
dc.type Journal Article 2018-06-05T07:29:01Z
dc.language.rfc3066 en
dc.identifier.mtmt 3360745
dc.identifier.wos 000429284100002
dc.identifier.pubmed 29674965
dc.contributor.department SZTE/ÁOK/Biokémiai Intézet
dc.contributor.department SE/AOK/I/Farmakológiai és Farmakoterápiás Intézet
dc.contributor.institution Szegedi Tudományegyetem
dc.contributor.institution Semmelweis Egyetem
dc.mtmt.swordnote Bencsik P and Kupai K have contributed equally to this work. Doman G and Ferdinandy P joint last authors.

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