Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

DEVELOPMENT OF NOVEL MATRIX METALLOPROTEINASE-2 INHIBITORS FOR CARDIOPROTECTION AGAINST ISCHEMIA/REPERFUSION INJURY: FROM CHEMICAL DESIGN TO PRECLINICAL PROOF-OF-CONCEPT STUDIES P. Bencsik 1,2 , T. Szabados 1,2 , É. Kenyeres 1 , K. Gömöri 1 , G. Dormán 3 , A. Görbe 1,4 , P. Ferdinandy 2,4 1 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; 2 Pharmahungary Group, Szeged, Hungary; 3 Targetex Biosciences Ltd., Dunakeszi, Hungary; 4 Department of Pharmacology and Pharmacotherapy, Semmelweiss University, Budapest, Hungary Background: Matrix metalloproteinase-2 (MMP-2) has been demonstrated to play a crucial role in the development of ischemia/reperfusion injury due to its enhanced activation, which leads to increased infarcted area. However, we have previously shown that there is no need for complete inhibition of MMP 2 to achieve cardioprotection since its moderate ( ∼ 20 – 25%) inhibition was sufficient to reduce infarct size in ex vivo and in vivo models of acute myocardial infarction (AMI). Therefore, we have designed novel MMP inhibitor compounds and performed a screening cascade to select potent MMP-2 inhibitors to test their cardioprotective effects in vivo. Methods: We selected 568 novel substituted carboxylic acid derivatives based on imidazole and thiazole scaffolds from molecular libraries and then tested in a screening cascade for MMP inhibition. Initially, we used in silico docking to the 3D model of MMP-2 followed by an in vitro screening based on a fluorescent assay employing MMP-2 catalytic domain as well as gelatin zymography for MMP-2 inhibitory tests to determine IC50 values. Seven compounds were selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotection and the most effective compounds (MMPI-1154, -1260, and -1248) were tested in an in vivo rat model of AMI in the presence or absence of hypercholesterolemia. Results: Ischemic preconditioning as positive control as well as MMPI-1154 and -1260 but not MMPI 1248 showed significant infarct size- limiting effects as compared to vehicle control at 1 and 3 µmol/kg, respectively, both in young healthy rats as well as in the age-matched controls of hypercholesterolemic group. However, in the presence of hypercholesterolemia, both inhibitors failed to reduce infarct size similarly to that of ischemic preconditioned group used as a positive control of cardioprotection. Conclusion: We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds were superior in efficacy in comparison to the conventional hydroxamic acid-type MMP inhibitors. MMPI-1154 and -1260 reduced infarct size reproducibly in normocholesterolemic rat AMI model. Although, hypercholesterolemia abolished their infarct size-limiting effect, the cardioprotective potential of our novel MMP-2 inhibitors cannot completely be excluded even in hypercholesterolemic comorbid models.

Keywords: matrix metalloproteinase; drug development; ischemia/reperfusion injury; mypcardial infarction; cardioprotection

Funding: This project was supported by the New National Excellence Program of the Ministry of Human Capacities (ÚNKP -21-5-SZTE-543), and by the Hungarian National Scientific Research Fund (OTKA-138223) as well as by the Faculty of Medicine of the University of Szeged (SZGYA 2020). PB was supported by the János Bolyai Research Scholarships of the Hungarian Academy of Sciences Bolyai (bo_481_21).

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