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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.
Highlights
Coronary heart disease (CHD) is the number one cause of death globally (Alwan et al, 2010)
This selection supported our initial hypothesis since acids are considered as weaker Zn2+ chelators than hydroxamic acids, which might be beneficial for achieving selectivity and in addition could be considered as a good indicator of the Matrix metalloproteinases (MMP)-2 inhibitory activity
We have successfully demonstrated the development of a novel, selective MMP-2 inhibitor for cardioprotection from an in silico compound library selection, through to the testing of the most promising compound against acute myocardial infarction, in an isolated rat heart model
Summary
Coronary heart disease (CHD) is the number one cause of death globally (Alwan et al, 2010). We have demonstrated that MMP-2 can be a promising biomarker for patients with coronary artery disease (Bencsik et al, 2015). We have previously reported that pharmacological inhibition of MMP-2 in rats evoked cardioprotection that is equivalent to ischemic preconditioning (Giricz et al, 2006; Bencsik et al, 2010). Our work has shown that hyperlipidemia abolished the beneficial effect of ischemic preconditioning, cardioprotection in the presence of hyperlipidemia was preserved during pharmacological inhibition of MMP-2 (Giricz et al, 2006). We can conclude that MMP2 inhibition is a promosing drug target since it works in the presence of a significant cardiovascular co-morbidity, namely hyperlipidemia (see for reviews Andreadou et al, 2017)
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